JP7724394B2 - isoindolinone compounds - Google Patents

Description

FIELD OF THE DISCLOSURE This disclosure relates to novel compounds as modulators of cereblon. This disclosure also relates to methods for preparing these compounds, compositions containing these compounds, and methods of using them to treat abnormal cell growth in mammals, particularly humans.

Background and Prior Art: The ubiquitin-proteasome system can be manipulated using a variety of small molecules to trigger the targeted degradation of specific proteins of interest. Facilitating the targeted degradation of pathogenic proteins using small molecule degraders is becoming known as a novel modality for disease treatment. One such modality relies on the use of low-molecular-weight compounds, which have been termed molecular glues (Tan et al. Nature 2007, 446, 640-645 and Sheard et al. Nature 2010, 468, 400-405), to redirect the activity of E3 ligases, such as cereblon (a phenomenon known as E3 reprogramming), promoting the poly-ubiquitination and ultimately proteasomal degradation of novel protein substrates involved in disease pathogenesis. The molecular glue binds to both the E3 ligase and the target protein, thereby mediating changes in the ligase surface, allowing it to interact with the target protein. Compounds specifically related to the E3 ligase cereblon are IMiDs (immunomodulatory imide drugs), including thalidomide, lenalidomide, and pomalidomide. These IMiDs have been approved by the FDA for use in hematological cancers. However, there remains a need for compounds that effectively target other diseases, especially other types of cancer.

Tan et al. Nature 2007, 446, 640-645 and Sheard et al. Nature 2010, 468, 400-405

SUMMARY OF THE DISCLOSURE Accordingly, it is an object of the present disclosure to advance the state of the art of cereblon modulators and to provide modulators preferably for novel uses in various diseases, particularly various cancers.
In advantageous embodiments, compounds are provided that target c-Myc-dependent cells more effectively than non-c-Myc-dependent cells.

In some advantageous embodiments, compounds are provided for use in the treatment of solid tumors, particularly for use in the treatment of breast cancer.

The present disclosure is directed in a first aspect to a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof:
(In the formula,
X ¹ is a linear or branched C _1-6 alkyl, C 3-6 cycloalkyl, —C _1-6 alkyl C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 alkyl C _6-10 aryl, C _1-6 alkyl 5-10 membered heteroaryl, and X ¹ is unsubstituted or is selected from the group consisting of halogen, linear or branched C _{1-6 alkyl, C 1-6 heteroalkyl} , CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —OC(O ₎ —C _1-4 alkylamino, —C(O)O—C substituted by one or more of C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-6 alkoxy or C _1-6 alkylhydroxy;
^X2 is hydrogen, _C6-10 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, _{C1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-C1-4 alkyl-} (4-8 membered heterocycloalkyl), -OC(O) _{-C1-4 alkyl-4-8} membered heterocycloalkyl or _C6 aryloxy, and ^X2 is unsubstituted or substituted by one or more of linear or branched _C1-6 alkyl, _NH2 , _NMe2 or 5-6 membered heterocycloalkyl;
and n is 0, 1 or 2.

In certain embodiments, X ¹ is a linear or branched C _1-4 alkyl, C _{3-6 cycloalkyl, —C 1-4} alkylC _3-6 cycloalkyl, C _{6 aryl, 5-10 membered heteroaryl, C 1-6} alkylC _{6 aryl, C 1-6 alkyl} 5-10 membered heteroaryl, and X ¹ is unsubstituted or selected from halogen, linear or branched C _1-4 alkyl, C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O _{)—C 1-6 alkyl} , —OC(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —C(O)O _— C and _{X2 is substituted by one or more of a linear or branched C1-6} alkyl, -COOH, -CHO, _-C1-6 alkylC(O)OH, _-C1-6 alkylC(O)O- _C1-6 alkyl, _NH2 , _C1-6 alkoxy or C1-6 alkylhydroxy; ^X2 is hydrogen, _C6 aryl, 5-10 membered heteroaryl, -O- ₍ 5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, _{C1-4 alkyl 4-8} membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O- _C1-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O) _-C1-4 alkyl-4-8 membered heterocycloalkyl or _C6 aryloxy; and ^X2 is unsubstituted or is substituted by one or more of a linear or branched _C1-6 alkyl, _NH2 , NMe It is substituted by one or more of _2- or 5- to 6-membered heterocycloalkyl, where n is 0, 1, or 2.

In some embodiments, n is 1. In some embodiments, n is 2.
More particularly, the present disclosure is directed to a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof:
(In the formula,
n is 1 or 2;
p is 0, 1, 2, 3, 4, 5, or 6;
Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl, C _3-6 cycloalkyl, Y ¹ is unsubstituted or is halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _{1-6 alkyl, —OC(O)—C 1-4} heteroalkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, _{—C 1-6 alkylC(O)OH, —C 1-6 alkylC (} O)O—C _1-6 alkyl, NH ₂ , C _1-6 alkoxy or C substituted by one or more of _1-6 alkylhydroxy, with the proviso that when p is 0, Y ¹ is not hydrogen;
^Y2 is hydrogen, _C6 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, _{C1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-C1-4 alkyl-} (4-8 membered heterocycloalkyl), -OC(O) _-C1-4 alkyl-4-8 membered heterocycloalkyl or _C6 aryloxy, ^Y2 is unsubstituted or substituted with one or more of linear or branched _C1-6 alkyl, _NH2 , _NMe2 or 5-6 membered heterocycloalkyl;
R ^a and R ^b are each independently selected from hydrogen and straight or branched C _1-4 alkyl, preferably hydrogen and methyl).

In some embodiments of the compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof, n is 1.
More particularly, the present disclosure is directed to compounds of formula IIIa, IIIb, or IIIc, or pharmaceutically acceptable salts or stereoisomers thereof:
(In the formula,
n is 1 or 2;
p is 0, 1 or 2;
one of w ¹ , w ² or w ³ is selected from C and N, and the other two of w ¹ , w ² or w ³ are C;
one or two of w ⁴ , w ⁵ , w ⁶ , w ⁷ are selected from C, O, N, NMe, NH or S, while two or three of w ⁴ , w ⁵ , w ⁶ and w ⁷ are C;
R ¹ , R ² , R ³ and R ⁴ are each hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ —O—(CH ₂ ) ₂ —OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C are independently selected from _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R ¹ , R ² , R ³ , R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl;
R ⁵ and R ⁶ are each independently selected from hydrogen, linear or branched C _1-4 alkyl, CF ₃ , CHF ₂ , halogen, preferably F, Cl, Br, more preferably F or Cl;
^X3 is absent, hydrogen, or 4- to 8-membered heterocycloalkyl, _C1-4 alkyl 4- to 8-membered heterocycloalkyl, -O-(4- to 8-membered heterocycloalkyl), _-C1-4 alkoxy-(4- to 8-membered heterocycloalkyl), 5- to 10-membered heteroaryl, -O-(5- to 10-membered heteroaryl), -OC(O)-C1-4 alkyl- _4- to 8-membered heterocycloalkyl, wherein ^X3 is unsubstituted or substituted with one or more of a linear or branched _C1-6 alkyl, _NH2 , _NMe2 , or 5- to 6-membered heterocycloalkyl;
Z is a straight or branched chain C _1-6 alkyl, or C _3-6 cycloalkyl or C _1-4 alkoxy, and Z is unsubstituted or substituted by C _1-4 alkyl.

In some embodiments of compounds of Formula IIIa, IIIb, or IIIc, or pharmaceutically acceptable salts or stereoisomers thereof, n is 1.

In certain embodiments of a compound of Formula IIIa, IIIb, or IIIc, or a pharmaceutically acceptable salt or stereoisomer thereof, p is 0 or 1.

In some embodiments of a compound of Formula IIIa, IIIb, or IIIc, or a pharmaceutically acceptable salt or stereoisomer thereof, p is 0.

In other embodiments of the compound of Formula IIIa, IIIb, or IIIc, or a pharmaceutically acceptable salt or stereoisomer thereof, p is 1.

In some embodiments of the compound of Formula IIIa, or a pharmaceutically acceptable salt or stereoisomer thereof, R ¹ , R ² , and R ³ are defined as above, and R ⁴ is hydrogen, wherein the aromatic ring contains four or five substituents that are not hydrogen.

In some embodiments of the compounds of Formula IIIa, or pharmaceutically acceptable salts or stereoisomers thereof, ^R1 and ^R2 are defined as above, and ^R3 and ^R4 are each hydrogen, where the aromatic ring contains three or four substituents that are not hydrogen.

More particularly, the present disclosure is directed to compounds of formulas IV, V, VI and VII, or pharmaceutically acceptable salts or stereoisomers thereof:
(In the formula,
W, ^W1 , ^W2 , and ^W3 are
(independently selected from the

In a second aspect, the present disclosure is directed to a composition comprising a compound according to any one of the embodiments described herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

In yet a further embodiment, the composition further comprises a second therapeutically active agent.

In a third aspect, the present disclosure is directed to a composition according to any of the embodiments described herein for use in therapy.

In a fourth aspect, certain embodiments include a compound of Formulas I-IV as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutically acceptable salt or composition thereof, for use in treating a disease associated with or caused by GSPT1, particularly a cancer associated with GSPT1, such as glioma, thyroid cancer, lung cancer, colorectal cancer, head and neck cancer, gastric cancer, liver cancer, pancreatic cancer, renal cancer, urothelial cancer, prostate cancer, testicular cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, melanoma, and multiple myeloma.

Some embodiments include a compound or composition according to any of the embodiments described herein for use in treating breast cancer.

In a fifth aspect, the present disclosure is directed to the use of a compound or composition according to any of the embodiments described herein for binding to cereblon, comprising administering a therapeutically effective amount of the composition to a subject.

Some embodiments include the use of a compound or composition according to any of the embodiments described herein to treat cancer, particularly breast cancer. Certain embodiments include the use of a composition according to any of the embodiments described herein to treat cancers associated with GSPT1, such as glioma, thyroid cancer, lung cancer, colorectal cancer, head and neck cancer, gastric cancer, liver cancer, pancreatic cancer, renal cancer, urothelial cancer, prostate cancer, testicular cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, melanoma, and multiple myeloma.

In a sixth aspect, the present disclosure is directed to a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound or composition of any of the embodiments described herein.
In some embodiments, the methods include a compound according to any of the embodiments described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, that binds to cereblon.
The present invention provides, for example, the following items.
(Item 1)
A compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof

wherein
X ¹ is a linear or branched C _1-6 alkyl, C 3-6 cycloalkyl, —C _1-6 alkyl C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 alkyl C _6-10 aryl, C _1-6 alkyl 5-10 membered heteroaryl, and X ¹ is unsubstituted or is selected from the group consisting of halogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) _{2 -OMe} , OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —C(O)O—C substituted by one or more of C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-6 alkoxy or C _1-6 alkylhydroxy;
X2 is hydrogen, C6-10 _aryl , 5-10 membered heteroaryl, -O-(5-10 ^membered heteroaryl), 4-8 membered heterocycloalkyl, C1-4 _alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-C1-4 alkyl-(4-8 membered heterocycloalkyl ₎ , -OC(O)-C1-4 _alkyl-4-8 membered heterocycloalkyl or C6 aryloxy _, and X2 ^is unsubstituted or substituted by one or more of linear or branched C1-6 _alkyl , NH2 _, NMe2 _or 5-6 membered heterocycloalkyl;
n is 0, 1 or 2;
A compound, or a pharmaceutically acceptable salt or stereoisomer thereof.
(Item 2)
X ¹ is linear or branched C _1-4 alkyl, C 3-6 cycloalkyl, —C _1-4 alkyl C _3-6 cycloalkyl, C ₆ aryl, 5-10 membered heteroaryl, C _1-6 alkyl C ₆ aryl , C 1-6 alkyl _5-10 membered heteroaryl, and X ¹ is unsubstituted or is selected from the group consisting of halogen, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C 1-6 alkyl, —OC(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino _, —C(O)O— _C substituted by one or more of C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-6 alkoxy or C _1-6 alkylhydroxy;
X2 is hydrogen, C6 _aryl , 5-10 membered heteroaryl, -O-(5-10 ^membered heteroaryl), 4-8 membered heterocycloalkyl, C1-4 _alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-C1-4 alkyl-(4-8 membered heterocycloalkyl ₎ , -OC(O)-C1-4 _alkyl-4-8 membered heterocycloalkyl or C6 _aryloxy , X2 ^is unsubstituted or substituted with one or more of linear or branched C1-6 _alkyl , NH2 _, NMe2 _or 5-6 membered heterocycloalkyl, and n is 0, 1 or 2;
Item 1, or a pharmaceutically acceptable salt or stereoisomer thereof.
(Item 3)
3. The compound according to item 1 or 2, wherein n is 1 or 2, preferably 1.
(Item 4)
A compound according to any of the preceding paragraphs of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof.

wherein
n is 1 or 2;
p is 0, 1, 2, 3, 4, 5, or 6;
Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or is halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF 2 , —O—(CH 2 ) 2 -OMe, OCF ₃ , _—CN , _—N ( _H )C(O)—C _1-6 alkyl, —OC(O)—C 1-6 alkyl, —OC(O )—C 1-4 heteroalkyl, —C(O)O—C _1-6 alkyl _, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _{1-6 alkyl} , NH ₂ or C substituted by one or more of _1-6 alkylhydroxy, with the proviso that when p is 0, Y ¹ is not hydrogen;
Y2 is hydrogen, C6 _aryl , 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C1-4 ^alkyl _4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-C1-4 alkyl-(4-8 membered heterocycloalkyl ₎ , -OC(O)-C1-4 _alkyl- 4-8 membered heterocycloalkyl or C6 _aryloxy , ^Y2 is unsubstituted or substituted with one or more of linear or branched C1-6 _alkyl , NH2 _, NMe2 _or 5-6 membered heterocycloalkyl;
R ^a and R ^b are each independently selected from hydrogen and linear or branched C _1-4 alkyl, preferably hydrogen and methyl;
A compound, or a pharmaceutically acceptable salt or stereoisomer thereof.
(Item 5)
5. The compound according to item 4, wherein n is 1, or a pharmaceutically acceptable salt or stereoisomer thereof.
(Item 6)
A compound according to any of the preceding paragraphs of formula IIIa', IIIb' or IIIc, or a pharmaceutically acceptable salt or stereoisomer thereof.

wherein
n is 1 or 2;
p is 0, 1 or 2;
one of w ¹ , w ² or w ³ is selected from C and N, and the other two of w ¹ , w ² or w ³ are C;
one or two of w ⁴ , w ⁵ , w ⁶ , w ⁷ are selected from C, O, N, NMe, NH or S, while two or three of w ⁴ , w ⁵ , w ⁶ and w ⁷ are C;
R ¹ , R ² , R ³ and R ⁴ are each independently selected from hydrogen, linear or branched C _1-6 alkyl, C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ —O—(CH ₂ ) ₂ —OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or R ¹ and R two of ^{R 2} , R ³ and R ⁴ taken together form a 5- to 6-membered heterocycloalkyl or a 5- to 6-membered heteroaryl;
R ⁵ and R ⁶ are each independently selected from hydrogen, linear or branched C _1-4 alkyl, CF ₃ , CHF ₂ , halogen, preferably F, Cl, Br, more preferably F or Cl;
X3 ^is absent, hydrogen, or 4- to 8-membered heterocycloalkyl, C1-4 _alkyl 4- to 8-membered heterocycloalkyl, -O-(4- to 8-membered heterocycloalkyl), -C1-4 _alkoxy- (4- to 8-membered heterocycloalkyl), 5- to 10-membered heteroaryl, -O-(5- to 10-membered heteroaryl), -OC(O)-C1-4 alkyl- _4- to 8-membered heterocycloalkyl, wherein X3 is unsubstituted or substituted with ^one or more of a linear or branched C1-6 _alkyl , NH2 _, NMe2 _, or 5- to 6-membered heterocycloalkyl;
Z is a linear or branched C _1-6 alkyl, or a C _3-6 cycloalkyl or a C _1-4 alkoxy, and Z is unsubstituted or substituted by a C _1-4 alkyl;
A compound, or a pharmaceutically acceptable salt or stereoisomer thereof.
(Item 7)
7. The compound according to item 6, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1.
(Item 8)
8. The compound according to item 6 or 7, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein p is 0 or 1.
(Item 9)
A compound according to any of the preceding paragraphs of formula IV, V, VI and VII, or a pharmaceutically acceptable salt or stereoisomer thereof.

wherein
W, ^W1 , ^W2 , ^W3 are

are independently selected from
A compound, or a pharmaceutically acceptable salt or stereoisomer thereof.
(Item 10)
W is,


10. The compound according to item 9, wherein:
(Item 11)
11. A composition comprising a compound according to any one of items 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof.
(Item 12)
12. The composition of claim 11, further comprising a pharmaceutically acceptable carrier.
(Item 13)
13. The composition of claim 11 or 12, further comprising a second therapeutically active agent.
(Item 14)
A compound according to items 1 to 10 or a composition according to any one of items 11 to 13 for use in therapy.
(Item 15)
14. A compound according to items 1 to 10 or a composition according to any one of items 11 to 13 for use in treating a disease associated with GSPT1.
(Item 16)
14. A compound according to items 1 to 10 or a composition according to any one of items 11 to 13 for use in the treatment of cancer, particularly breast cancer.
(Item 17)
13. Use of a compound according to items 1 to 10 or a composition according to items 11 or 12 for binding to cereblon, comprising the step of administering a therapeutically effective amount of said composition to a subject.
(Item 18)
18. Use according to item 17 for treating cancer, in particular breast cancer.
(Item 19)
13. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to items 1 to 10 or a composition according to any one of items 11 or 12.
(Item 20)
19. The method of claim 18, wherein the compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof, binds to the cereblon.

Not specified. Not specified.

DETAILED DESCRIPTION OF THE DISCLOSURE Unless otherwise specified, the following general definitions apply to all compounds of the present disclosure according to this description.

The term "compounds of the present disclosure," as used herein, refers to any of the compounds represented by Formulas I-IV and specific examples disclosed herein.

"Independently of each other" means that if a group occurs more than once in any compound, its definition at each occurrence is understood to be independent of any other occurrence.

It is further understood that dashed lines (or wavy lines across bonds) illustrate binding sites for residues (i.e., subformulas).

It is further understood that the abbreviations "C" and "N" represent all possible degrees of saturation, which saturation does not normally result in radicals, nitrenes, or carbenes, i.e., N includes -NH- and -N=, and C includes -CH ₂ - and =CH-. Furthermore, "C" as an atom in an aromatic or heteroaromatic ring bearing a substituent R ^x in any suitable position includes =CH- and =CR ^x -.

The term " _C6-10 aryl" refers to a fully or partially aromatic ring system having 6, 7, 8, _{9, or 10 ring atoms, including monocyclic and fused bicyclic rings. Examples of C6-10} aryl include, for example, phenyl, indenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl.

The term "5- to 10-membered heteroaryl" refers to a fully or partially aromatic ring system having 5, 6, 7, 8, 9, or 10 ring atoms selected from C, N, O, or S, preferably C, N, or O, more preferably C or N; the number of N atoms is preferably 0, 1, 2, or 3, and the number of O and S atoms is 0, 1, or 2, respectively. The term "5- to 10-membered heteroaryl" includes monocyclic and fused bicyclic rings. A fully aromatic ring system is preferably a monocyclic ring having 5 or 6 ring atoms selected from C, N, O, or S, preferably C, N, or O, more preferably C or N; the number of N atoms is preferably 0, 1, 2, or 3, and the number of O and S atoms is 0, 1, or 2, respectively. The partial aromatic ring system is preferably a fused bicyclic ring having 8 or 9 ring atoms selected from C, N, O, or S, preferably C, N, or O, more preferably C or O. Examples of "5- to 10-membered heteroaryl" include furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, indolyl, quinazolinyl, oxazolinyl, isoxazolinyl, indazolinyl, isothiazolyl, 1,3-benzodioxolyl, and the like. Preferred examples of "heteroaryl" include pyridinyl, isothiazolyl, thiazolyl, pyrazolyl, thienyl, prolyl, isoxazolinyl, and 1,3-benzodioxolyl.

The term "C _3-6 cycloalkyl" refers to a saturated alkyl ring system containing 3, 4, 5 or 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "4- to 8-membered heterocycloalkyl" refers to a ring system having 4, 5, 6, 7, or 8 ring atoms selected from C, N, O, or S, preferably C, N, or O, where the number of N atoms is 0, 1, or 2, and the number of O and S atoms is 0, 1, or 2, respectively. The term "4- to 8-membered heterocycloalkyl" preferably includes fully saturated monocyclic, fused, bridged, or spiro-bicyclic rings. Examples of 5- to 6-membered heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl, piperidinyl, morpholinyl, and the like. Preferred 4- to 8-membered heterocycloalkyl include 5-membered heterocycloalkyl having 1 or 2 N-atoms such as pyrrolidinyl, 6-membered heterocycloalkyl having N and O-atoms such as morpholinyl, piperidinyl, piperazinyl, dioxanyl, 7-membered heterocycloalkyl having N and O-atoms such as 1 N and 1 O-atom such as 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 1,4-diazabicyclo[3.2.1]octan-4-yl, 3-methyl-3-azabicyclo[3.1.0]hexan-1-yl, and 8-membered heterocycloalkyl having N and O-atoms such as 1 N and 1 O-atom such as 8-oxa-3-azabicyclo[3.2.1]octan-3-yl. The term "C _1-4 alkyl 4-8 membered heterocycloalkyl" refers to an alkyl, as defined below, having from 1 to 4 carbon atoms, attached to a 4-8 membered heterocycloalkyl, as defined above. Preferably, the C _1-4 alkyl can be C 1 , resulting in -(CH ₂ )-(4-8 membered heterocycloalkyl), or C ₂ , resulting in -(CH ₂ ) ₂ -(4-8 membered heterocycloalkyl), or C ₃ , resulting in -(CH _{2 ) 3} -(4-8 membered heterocycloalkyl). Examples include -( _CH2 )-morpholinyl, -( _CH2 ) ₂ -morpholinyl, -( _CH2 ) ₃ -morpholinyl, -( _CH2 ) ₄ -morpholinyl, -( _CH2 )-piperazinyl, -( _CH2 ) ₂ -N-methyl-piperazinyl, -( _CH2 ) ₃ -piperazinyl or -( _CH2 ) ₄ -piperazinyl. The term " _C1-4 alkoxy 4-8 membered heterocycloalkyl" refers to a 4-7 membered heterocycloalkyl as defined above that is linked to its adjacent group via a _C1-4 alkoxy group. Preferably, the C _1-4 alkoxy can be C ₁ , resulting in -(O-CH ₂ )-(4- to 8-membered heterocycloalkyl), or C 2, resulting in -(O-CH ₂ ) ₂ -(4- to 8-membered heterocycloalkyl), or C _3, resulting in -(O-CH ₂ ) ₃ -( _4- to 8-membered heterocycloalkyl). Examples include -(O-CH ₂ )-(N-morpholinyl), -(O-CH ₂ ) ₂ -(N-morpholinyl). The term "-O-(4- to 8-membered heterocycloalkyl)" refers to a 4- to 8-membered heterocycloalkyl as defined above, linked to its adjacent group via an -O- group. Examples include -O-morpholinyl, -O-piperazinyl, -O-pyrrolidinyl, and the like. The term "-O(CO) _{-Ci_4} alkyl 4 to 7 membered heterocycloalkyl" refers to a 4 to 8 membered heterocycloalkyl as defined above linked to its adjacent group via an -O(CO) _{-Ci_4} alkyl group. Preferably, "-O(CO)-Ci_4 alkyl" can be C1, resulting in -(O(CO)-CH2)-( ₄ to 8 membered heterocycloalkyl), or _C2 , resulting in -(O(CO) _-CH2 ) _{2- (} 4 to 8 membered heterocycloalkyl), or _C3 , resulting in -(O(CO) _-CH2 ) _3- (4 to 8 membered _{heterocycloalkyl} ). Examples include -(O(CO) _-CH2 )-(N-morpholinyl) or -(O(CO) _-CH2 - _CH2 )-(N-morpholinyl). The term "halogen" or "hal" as used herein can be fluoro, chloro, bromo or iodo, preferably fluoro, chloro or bromo, more preferably fluoro or chloro.

The term "alkyl," as used herein, refers to a fully saturated, branched or unbranched hydrocarbon moiety. The terms "C _1-4 alkyl" and "C _1-6 alkyl" refer to a fully saturated, branched or unbranched hydrocarbon moiety having 1, 2, 3, or 4, and 1, 2, 3, 4, 5, or 6 carbon atoms, respectively. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, iso-hexyl, or neohexyl.

The term "C _1-4 alkoxy" refers to an unsubstituted or substituted alkyl chain linked to the remainder of the molecule via an oxygen atom, particularly methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy and t-butoxy.

The term "C _1-4 alkyl-C _1-4 alkoxy" refers to a _C 1-4 alkyl group functionalized with _a C 1-4 alkoxy group, for example, -CH ₂ -O-CH ₃ , -(CH ₂ ) _{2 -O} -CH ₃ , -(CH ₂ ) _{3 -O} - _{CH 3} , -(CH ₂ ) 4 -O-CH ₃ , -CH ₂ -O-CH _{2 -CH 3} , -CH ₂ -O-(CH ₂ ) ₂ -CH ₃ , -CH ₂ -O-(CH 2 ) _{3 -CH 3} , and branched isomers thereof.

The term "C _1-6 heteroalkyl" refers to an alkyl, as defined below, having 1, 2, 3, 4, 5, or 6 carbon atoms, wherein at least one or at least two carbon atoms are replaced by a heteroatom such as N, O, S, preferably N, O. It is understood that the heteroatom may be further substituted by one or two C _1-6 alkyls. Those skilled in the art will also recognize that the term "substituted" includes substitution at one or more C-atoms (e.g., -CH ₂ -CH ₂ -) by heteroatoms (e.g., -CH ₂ -CH(Het)-), and/or replacement of one or more C-atoms within the alkyl chain (e.g., -CH ₂ -CH ₂ -CH ₂ ) (e.g., to give -CH ₂ -Het-CH ₂ -). Examples include -(CH ₂ ) ₂ -O-Me, -(CH ₂ ) ₃ -O-Me, -(CH)(OMe)(CH ₃ ), -(CH ₂ ) ₂ -O-CH ₂ Me, -(CH ₂ ) ₂ -NMe ₂ , -(CH ₂ )-NMe ₂ , -(CH ₂ ) ₂ -NEt ₂ , -(CH ₂ )-NEt ₂ , -O-(CH ₂ ) ₃ -NMe ₂ , and the like.

The term "C _1-4 alkylamino" refers to a fully saturated branched or unbranched C 1-4 alkyl substituted with at least one, and preferably only one, amino group, alkylamino group, or dialkylamino group such as NH ₂ , HN(C _1-4 alkyl) or N(C _1-4 alkyl) _2. Thus, C _1-4 alkylamino refers to C _1-4 alkylamino, C _1-4 alkyl-(C _1-4 alkyl)amino, C _1-4 alkyl-( _{C 1-4 dialkyl} )amino. Examples include, but are not limited to, dimethylamino, methylaminomethyl, dimethylamonimethyl, aminomethyl, dimethylaminoethyl, aminoethyl, methylaminoethyl, n-propylamino, iso-propylamino, n-butylamino, sec-butylamino, iso-butylamino, tert-butylamino.

Based on the definitions provided throughout this application, one of ordinary skill in the art will recognize which combinations are synthetically feasible and practical; for example, combinations of groups that typically result in heteroatoms directly linked to each other are not contemplated.

In a first aspect, the present invention is directed to a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof:
(In the formula,
X ¹ is a linear or branched C _1-6 alkyl, C 3-6 cycloalkyl, —C _1-6 alkyl C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 alkyl C _6-10 aryl, C _1-6 alkyl 5-10 membered heteroaryl, and X ¹ is unsubstituted or is selected from the group consisting of halogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) _{2 -OMe} , OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —C(O)O—C substituted by one or more of C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-6 alkoxy or C _1-6 alkylhydroxy;
^X2 is hydrogen, _C6-10 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, _{C1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-C1-4 alkyl-} (4-8 membered heterocycloalkyl), -OC(O) _{-C1-4 alkyl-4-8} membered heterocycloalkyl or _C6 aryloxy, and ^X2 is unsubstituted or substituted by one or more of linear or branched _C1-6 alkyl, _NH2 , _NMe2 or 5-6 membered heterocycloalkyl;
n is 0, 1 or 2).

In preferred embodiments of compounds of Formula I, n is 1 or 2.

In a further embodiment of the compound of Formula I, n is 1.

In a further embodiment of the compound of Formula I, n is 2.

In more particular embodiments of compounds of formula I, X ¹ is linear or branched C _1-6 alkyl, C _{3-6 cycloalkyl, —C 1-6} alkylC _3-6 cycloalkyl, C ₆ aryl, 5-10 membered heteroaryl, C _1-6 alkylC 6-10 aryl, C _1-6 alkyl _5-10 membered heteroaryl, and X ¹ is unsubstituted or is selected from the group consisting of halogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O) _{—C 1-6 alkyl, —OC(O)—C 1-6 alkyl ,} —OC(O)—C and X 2 is substituted by _{one or more of 1-4} alkylamino, -C(O)O-C _1-6 alkyl, -COOH, -CHO, -C _1-6 alkylC(O)OH, -C _1-6 alkylC(O)O-C _1-6 alkyl, NH ₂ , C _1-6 alkoxy or C _1-6 alkylhydroxy; X ² is hydrogen, C _6-10 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _1-6 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-C _1-6 alkyl-(4-8 membered heterocycloalkyl), -OC(O)-C _1-6 alkyl-4-8 membered heterocycloalkyl or C ₆ aryloxy; and X ² is unsubstituted or is a straight or branched chain C _1-6 alkyl, NH ₂ , NMe It is substituted by one or more of _2- or 5- to 6-membered heterocycloalkyl, where n is 0, 1, or 2.

In more particular embodiments of the compound of formula I, X ¹ is linear or branched C _1-6 alkyl, C _3-6 cycloalkyl, —C _1-6 alkylC 3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 alkylC 6 aryl; X ¹ is unsubstituted or substituted with one or more _{of halogen, linear or branched C 1-6 alkyl, linear or branched C 1-6 heteroalkyl , CF 3} , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , —CN, —OC(O)—C _1-6 alkylamino, —CHO, —C _1-6 alkylC(O)OH, NH ₂ , C _1-6 alkoxy, or C _1-6 alkylhydroxy; and X ² is hydrogen, C _and n is _{0 , 1 , or} ² _.

In more particular embodiments of compounds of formula I, X ¹ is linear or branched C _1-4 alkyl, C _{3-6 cycloalkyl, —C 1-4 alkylC 3-6} cycloalkyl, C ₆ aryl, 5-10 membered heteroaryl, C 1-6 alkylC ₆ aryl, C _1-6 alkyl 5-10 membered heteroaryl, and X ¹ is unsubstituted or is _{selected from the group consisting of halogen, linear or branched C 1-4 alkyl} , linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF 2 , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , _{C 1-6 alkylamino} , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O) _{—C 1-6 alkyl} , —OC(O)—C _1-4 alkylamino, —C(O)O—C and _{X2 is substituted by one or more of a linear or branched C1-6} alkyl, -COOH, -CHO, _-C1-6 alkylC(O)OH, _-C1-6 alkylC(O)O- _C1-6 alkyl, _NH2 , _C1-6 alkoxy or C1-6 alkylhydroxy; ^X2 is hydrogen, _C6 aryl, 5-10 membered heteroaryl, -O- ₍ 5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, _{C1-4 alkyl 4-8} membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O- _C1-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O) _-C1-4 alkyl-4-8 membered heterocycloalkyl or _C6 aryloxy; and ^X2 is unsubstituted or is substituted by one or more of a linear or branched _C1-6 alkyl, _NH2 , NMe It is substituted by one or more of _2- or 5- to 6-membered heterocycloalkyl, where n is 0, 1, or 2.

In more particular embodiments of compounds of formula I, X ¹ is linear or branched C _1-4 alkyl, C _{3-6 cycloalkyl, —C 1-4} alkylC _3-6 cycloalkyl, C ₆ aryl, 5-10 membered heteroaryl, C _1-6 alkylC ₆ aryl; X ¹ is unsubstituted or substituted with one or more _of halogen, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , —CN, —OC(O)—C _1-4 alkylamino, —CHO, —C _1-6 alkylC(O)OH, NH ₂ , C _1-6 alkoxy, or C _1-6 alkylhydroxy; and X ² is hydrogen, C and n is 0, 1, or 2. In some embodiments, X 2 is unsubstituted or substituted with one or more of a linear or branched C _1-6 alkyl, NH ₂ , NMe ₂ , or _5-6 membered heterocycloalkyl; and n is 0, _{1, or 2} ^.

In more particular embodiments of compounds of formula I, X ¹ is linear or branched C _1-6 alkyl, C _{3-6 cycloalkyl, —C 1-6} alkylC _3-6 cycloalkyl, C ₆ aryl, 5-10 membered heteroaryl, C _1-6 alkylC 6-10 aryl, C _1-6 alkyl _5-10 membered heteroaryl, and X ¹ is unsubstituted or is selected from the group consisting of halogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O) _{—C 1-6 alkyl, —OC(O)—C 1-6 alkyl ,} —OC(O)—C and X 2 is substituted by _{one or more of 1-4} alkylamino, -C(O)O-C _1-6 alkyl, -COOH, -CHO, -C _1-6 alkylC(O)OH, -C _1-6 alkylC(O)O-C _1-6 alkyl, NH ₂ , C _1-6 alkoxy or C _1-6 alkylhydroxy; X ² is hydrogen, C _6-10 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _1-6 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-C _1-6 alkyl-(4-8 membered heterocycloalkyl), -OC(O)-C _1-6 alkyl-4-8 membered heterocycloalkyl or C ₆ aryloxy; and X ² is unsubstituted or is a straight or branched chain C _1-6 alkyl, NH ₂ , NMe It is substituted by one or more of _2- or 5- to 6-membered heterocycloalkyl, and n is 1.

In more particular embodiments of compounds of formula I, X ¹ is linear or branched C _1-6 alkyl, C _3-6 cycloalkyl, —C 1-6 alkylC _3-6 cycloalkyl, C _{6-10 aryl, 5-10 membered heteroaryl, C 1-6 alkylC} 6 aryl; X ¹ is unsubstituted or substituted with one or more of halogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF _{2 ,} —O—(CH ₂ ) ₂ -OMe, OCF ₃ , _—CN , —OC(O)—C _1-6 alkylamino, —CHO, —C _1-6 alkylC(O)OH, NH ₂ , C _1-6 alkoxy, or C _1-6 alkylhydroxy; and X ² is hydrogen, C _{and n is 1 .} ^​ _{​ ​}

In more particular embodiments of compounds of formula I, X ¹ is linear or branched C _1-4 alkyl, C _{3-6 cycloalkyl, —C 1-4 alkylC 3-6} cycloalkyl, C ₆ aryl, 5-10 membered heteroaryl, C 1-6 alkylC ₆ aryl, C _1-6 alkyl 5-10 membered heteroaryl, and X ¹ is unsubstituted or is _{selected from the group consisting of halogen, linear or branched C 1-4 alkyl} , linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF 2 , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , _{C 1-6 alkylamino} , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O) _{—C 1-6 alkyl} , —OC(O)—C _1-4 alkylamino, —C(O)O—C and _{X2 is substituted by one or more of a linear or branched C1-6} alkyl, -COOH, -CHO, _-C1-6 alkylC(O)OH, _-C1-6 alkylC(O)O- _C1-6 alkyl, _NH2 , _C1-6 alkoxy or C1-6 alkylhydroxy; ^X2 is hydrogen, _C6 aryl, 5-10 membered heteroaryl, -O- ₍ 5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, _{C1-4 alkyl 4-8} membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O- _C1-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O) _-C1-4 alkyl-4-8 membered heterocycloalkyl or _C6 aryloxy; and ^X2 is unsubstituted or is substituted by one or more of a linear or branched _C1-6 alkyl, _NH2 , NMe It is substituted by one or more of _2- or 5- to 6-membered heterocycloalkyl, and n is 1.

In more particular embodiments of compounds of formula I, X ¹ is linear or branched C _1-4 alkyl, C _{3-6 cycloalkyl, —C 1-4} alkylC _3-6 cycloalkyl, C ₆ aryl, 5-10 membered heteroaryl, C _1-6 alkylC ₆ aryl; X ¹ is unsubstituted or substituted with one or more _of halogen, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , —CN, —OC(O)—C _1-4 alkylamino, —CHO, —C _1-6 alkylC(O)OH, NH ₂ , C _1-6 alkoxy, or C _1-6 alkylhydroxy; and X ² is hydrogen, C and n is 1. In some embodiments, X 2 is unsubstituted or ^substituted with one or more _{of a} linear or branched C _1-6 alkyl, NH _{2 ,} NMe ₂ or _5-6 membered heterocycloalkyl.

In an even more particular embodiment, the compound of formula I is a compound of formula I′, or a pharmaceutically acceptable salt or stereoisomer thereof:
(In the formula,
X is a linear or branched C _1-6 alkyl, C _{3-6 cycloalkyl, C 1-6} alkyl C _3-6 cycloalkyl, C _{6-10 aryl, 5-10 membered heteroaryl, C 1-6 alkylaryl} , C _1-6 alkyl 5-10 membered heteroaryl, and X is unsubstituted or selected from halogen, linear or branched C _{1-6 alkyl, C 6-10 aryl} , 5-10 membered heteroaryl, C _1-6 heteroalkyl, 4-7 membered heterocycloalkyl, C _1-4 alkyl _4-7 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF 3 , C _1-6 alkylamino, —CN, —OC(O) _{—C 1-6 alkyl, —N(H)C(O)—C 1-6 alkyl ,} —C(O)O—C substituted by one or more of C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-6 alkoxy, C _1-6 alkylhydroxy or C ₆ aryloxy;
n is 0, 1 or 2).

In preferred embodiments of compounds of formula I', n is 1 or 2, and more preferably, n is 1.

In a further embodiment of the compound of Formula I', n is 1.

In more particular embodiments of compounds of formula I', X is linear or branched C _1-6 alkyl, C _3-6 cycloalkyl, -C 1-6 alkylC _3-6 cycloalkyl, C 6-10 aryl, where X is unsubstituted or halogen, particularly F, Cl, Br, linear or branched C _1-6 alkyl, C _6-10 aryl, 4-7 membered heterocycloalkyl, C _1-4 alkyl _4-7 membered heterocycloalkyl, CF ₃ , CHF ₂ , -O-(CH _{2 ) 2 -OMe} , OCF ₃ , C _1-6 alkylamino, -CN, -OC(O)-C _1-6 alkyl, -C(O)O-C _1-6 alkyl, -COOH, -C _1-6 alkylC(O)OH, -C _1-6 alkylC(O)O-C _1-6 alkyl, NH ₂ , C It is substituted by one or more of _1-6 alkylhydroxy, C _1-6 alkoxy or C _1-6 hydroxy.

In more particular embodiments of compounds of formula I', X is linear or branched C _1-6 alkyl, C _3-6 cycloalkyl, -C _{1-6 alkylC 3-6} cycloalkyl, C _{6-10 aryl, and X is unsubstituted or substituted with one or more of halogen, particularly F, Cl, Br, linear or branched C 1-6 alkyl} , C _6-10 aryl, CF ₃ , OCF ₃ , C _1-6 alkylamino, -CN, C _1-6 alkoxy _.

In a further embodiment of the compound of formula I', n is 1 and X is a linear or branched C _1-6 alkyl, C _3-6 cycloalkyl, -C 1-6 alkylC _{3-6 cycloalkyl, C 6-10 aryl} , where X is unsubstituted or is halogen, particularly F, Cl, Br, linear or branched C _1-6 alkyl, C _6-10 aryl, 4-7 membered heterocycloalkyl, C _1-4 alkyl 4-7 membered heterocycloalkyl, CF ₃ , CHF ₂ , _-O- (CH ₂ ) ₂ -OMe, OCF ₃ , C 1-6 alkylamino, -CN, -N(H)C(O)-C _1-6 alkyl, -OC(O)-C _1-6 alkyl, -C(O)O-C _1-6 alkyl, -COOH, _{-C 1-6 alkylC} (O)OH, -C It is substituted by one or more of _1-6 alkylC(O)O-C _1-6 alkyl, NH ₂ , C _1-6 alkylhydroxy, C _1-6 alkoxy.

In a further embodiment of the compound of formula I', n is 1 and X is a linear or branched C _1-6 alkyl, C _3-6 cycloalkyl, -C _1-6 alkylC _3-6 cycloalkyl, C _6-10 aryl, where X is unsubstituted or substituted with one or more of halogen, particularly F, Cl, Br, linear or branched C _1-6 alkyl, C _6-10 aryl, CF ₃ , OCF ₃ , C _1-6 alkylamino, -CN, C _1-6 alkoxy.

In more particular embodiments of compounds of formula I', X is linear or branched C _1-4 alkyl, C _3-4 cycloalkyl, C _1-4 alkyl C _3-6 cycloalkyl, C ₆ aryl, 5-10 membered heteroaryl, C 1-6 alkylaryl, C _1-6 alkyl 5-10 membered heteroaryl; X is halogen, particularly F, Cl, Br, linear or branched C _1-4 alkyl, C ₆ aryl, 5-10 membered heteroaryl, _4-6 membered heterocycloalkyl, C _1-4 alkyl 4-6 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-4 alkylhydroxy, C _1-4 alkoxy, and n is 0, 1 or 2.

In more particular embodiments of compounds of formula I', X is linear or branched C _1-4 alkyl, C _3-4 cycloalkyl, C _1-4 alkyl C _3-6 cycloalkyl, C ₆ aryl, 5-10 membered heteroaryl, C 1-6 alkylaryl, C _1-6 alkyl 5-10 membered heteroaryl, X is optionally substituted with one or more of halogen, particularly F, Cl, Br, linear or branched C _1-4 alkyl, C ₆ aryl, 5-10 membered heteroaryl, CF ₃ , _{OCF 3} , C _1-4 alkylamino, —CN, C _1-4 alkoxy, and n is 0, 1, or 2.

In more particular embodiments of compounds of formula I', X is linear or branched C _1-4 alkyl, C _{3-4 cycloalkyl, C 1-4} alkyl C _3-6 cycloalkyl, C 6 aryl, _{5-10 membered heteroaryl, C 1-6 alkylaryl} , C _1-6 alkyl 5-10 membered heteroaryl; X is halogen, particularly F, Cl, Br, linear or branched C _1-4 alkyl, C ₆ aryl, 5-10 membered heteroaryl, morpholinyl, -(CH ₂ )-morpholinyl, piperazinyl, -(CH 2 )-piperazinyl, CF ₃ , CHF ₂ , -O-(CH ₂ ) ₂ -OMe, OCF ₃ , C _1-6 alkylamino, -CN, -OC(O ₎ -C _1-6 alkyl, -N(H)C(O) _{-C and} n _{is 0 , 1 or 2 .}

In certain embodiments of compounds of formula I', X is linear or branched C _1-4 alkyl, C _{3-4 cycloalkyl, C 1-4} alkyl C _3-6 cycloalkyl, C 6 aryl, 5-10 membered heteroaryl, C _1-6 alkylaryl, C _1-6 alkyl _5-10 membered heteroaryl; X is halogen, particularly F, Cl, Br, linear or branched C _1-4 alkyl, C ₆ aryl, 5-10 membered heteroaryl, 4-6 membered heterocycloalkyl, C _1-4 alkyl _4-6 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-4 alkylhydroxy, C _1-4 alkoxy, and n is 1.

In certain embodiments of compounds of formula I', X is linear or branched C _1-4 alkyl, C 3-4 cycloalkyl, C _1-4 alkyl C 3-6 cycloalkyl, C 6 aryl, _{5-10 membered heteroaryl, C 1-6 alkylaryl} , C _1-6 alkyl _5-10 membered heteroaryl; X is halogen, particularly F, Cl, Br, linear or branched C _1-4 alkyl, C ₆ aryl, 5-10 membered heteroaryl, morpholinyl, -(CH ₂ )-morpholinyl, piperazinyl, -(CH 2 ₎ -piperazinyl, CF ₃ , CHF ₂ , -O-(CH ₂ ) ₂ -OMe, OCF ₃ , C _1-6 alkylamino, -CN, -OC(O)-C _1-6 alkyl, -N(H)C(O) _{-C and n is 1 . ​ ​ ​}

In certain embodiments of compounds of formula I', X is linear or branched C _1-4 alkyl, C _3-4 cycloalkyl, C _1-4 alkyl C _3-6 cycloalkyl, C ₆ aryl, 5-10 membered heteroaryl, C _{1-6 alkylaryl, C 1-6} alkyl 5-10 membered heteroaryl, where X is optionally substituted with one _{or more of halogen, particularly F, Cl, Br, linear or branched C 1-4 alkyl} , C ₆ aryl, 5-10 membered heteroaryl, CF ₃ , OCF ₃ , C _1-4 alkylamino, —CN, C _1-4 alkoxy, and n is 1.

In other embodiments of compounds of formula I', X is linear or branched C _1-4 alkyl, C 3-4 cycloalkyl, C _1-4 alkyl C _3-6 cycloalkyl, C ₆ aryl; X is halogen, particularly F, Cl, Br, linear or branched C _1-4 alkyl, C ₆ aryl, 4-6 membered heterocycloalkyl, C _1-4 alkyl 4-6 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, _{—C 1-6 alkylC} (O)O—C _1-6 alkyl, NH ₂ , C _1-4 alkylhydroxy, C _1-4 alkoxy, and n is 1.

In other embodiments of compounds of formula I', X is linear or branched C _1-4 alkyl, C 3-4 cycloalkyl, C _1-4 alkylC _3-6 cycloalkyl, C ₆ aryl; X is halogen, particularly F, Cl, Br, linear or branched C _{1-4 alkyl, C 6} aryl, morpholinyl, -(CH ₂ )-morpholinyl, piperazinyl, -(CH ₂ )-piperazinyl, CF ₃ , CHF ₂ , -O-(CH ₂ ) ₂ -OMe, OCF ₃ , _{C 1-6 alkylamino} , -CN, -OC(O)-C _1-6 alkyl, -N(H)C(O)-C _1-6 alkyl, -C(O)O-C _1-6 alkyl, -COOH, -C _1-6 alkylC(O)OH, _-C Optionally substituted with one or more of _1-6 alkylC(O)O-C _1-6 alkyl, NH ₂ , C _1-4 alkylhydroxy, C _1-4 alkoxy; and n is 1.

In other embodiments of compounds of formula I', X is linear or branched C _1-4 alkyl, C _3-4 cycloalkyl, C 1-4 alkyl C _3-6 cycloalkyl, C ₆ aryl, wherein X is optionally substituted with one or more of halogen, particularly F, Cl, Br, linear or branched C _1-4 alkyl, C ₆ aryl, CF ₃ , OCF ₃ , C _1-4 alkylamino, —CN, _{C 1-4 alkoxy} , and n is 1.

More particularly, the present disclosure is directed to a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof:
(In the formula,
n is 1 or 2;
p is 0, 1, 2, 3, 4, 5, or 6;
Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or is halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C 1-6 alkyl, —OC(O)—C _1-4 heteroalkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O _{—C 1-6 alkyl, NH 2 , C 1-6 alkoxy or C} substituted by one or more of _1-6 alkylhydroxy, with the proviso that when p is 0, Y ¹ is not hydrogen;
^Y2 is hydrogen, _C6 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, _{C1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-C1-4 alkyl-} (4-8 membered heterocycloalkyl), -OC(O) _-C1-4 alkyl-4-8 membered heterocycloalkyl or _C6 aryloxy, ^Y2 is unsubstituted or substituted with one or more of linear or branched _C1-6 alkyl, _NH2 , _NMe2 or 5-6 membered heterocycloalkyl;
R ^a , R ^b are each independently selected from hydrogen and straight or branched C _1-4 alkyl, preferably hydrogen or methyl).

For compounds of formula II, it is understood that when Y ¹ is hydrogen, Y ² is absent.

In some particular embodiments of compounds of Formula II, n is 1.

In more specific embodiments of compounds of Formula II, p is 0, 1, or 2.

In some particular embodiments of compounds of Formula II, p is 0 or 1.

In other embodiments of compounds of Formula II, n is 1 and p is 0, 1, or 2.

In certain embodiments of compounds of Formula II, n is 1 and p is 0 or 1.

In more particular embodiments of compounds of formula II, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl; Y ¹ is unsubstituted or substituted with one or more of halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —OC(O)—C _1-4 heteroalkyl, —CHO, —C _1-6 alkylC(O)OH, NH ₂ or C _1-6 alkylhydroxy; and Y ² is hydrogen, C ₆ aryl, 5-10 membered heteroaryl, —O—(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, —O—(4-8 membered heterocycloalkyl), —O—C _1-4 alkyl-(4-8 membered heterocycloalkyl), —OC(O)—C _1-4 alkyl-4-8 membered heterocycloalkyl, and Y ² is unsubstituted or substituted with one or more of a linear or branched C _1-6 alkyl, NH ₂ , NMe ₂ or a 5-6 membered heterocycloalkyl.

In more particular embodiments of compounds of formula II, n is 1, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _{1-6 alkyl, —OC(O)—C 1-4} heteroalkyl, —C(O)O—C 1-6 alkyl, —COOH _, —CHO, _{—C 1-6 alkylC(O)OH, —C 1-6 alkylC (} O)O—C _1-6 alkyl, NH ₂ , C _1-6 alkoxy, or C _1-6 alkylhydroxy; Y ² is hydrogen, C ₆ aryl, 5-10 membered heteroaryl, —O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _{1-4 alkyl 4-8 membered heterocycloalkyl, —O-(4-8 membered heterocycloalkyl), —O—C 1-4 alkyl-} (4-8 membered heterocycloalkyl), —OC(O)—C _{1-4 alkyl-4-8} membered heterocycloalkyl, or C ₆ aryloxy; and Y ² is unsubstituted or substituted by one or more of linear or branched C _1-6 alkyl, NH ₂ , NMe ₂ or 5-6 membered heterocycloalkyl.

In more particular embodiments of compounds of formula II, n is 1, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or substituted with one or more of halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —OC(O)—C _1-4 heteroalkyl, —CHO, —C _1-6 alkylC(O)OH, NH ₂ or C _1-6 alkylhydroxy, and Y ² is hydrogen C ₆ aryl, 5-10 membered heteroaryl, —O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-Ci _-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O)-Ci _-4 alkyl-4-8 membered heterocycloalkyl, and ^Y2 is unsubstituted or substituted with one or more of a linear or branched Ci _-6 alkyl, _NH2 , _NMe2 or a 5-6 membered heterocycloalkyl.

In more particular embodiments of compounds of formula II, p is 0, 1, or 2, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or is halogen, preferably F, Cl, or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —OC(O)—C _1-4 heteroalkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C and Y2 is unsubstituted or substituted by one or more of linear or branched _C1-6 alkyl, _NH2 , _C1-6 alkoxy or _C1-6 alkylhydroxy; ^Y2 is hydrogen, _C6 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, _C1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O- _C1-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O) _-C1-4 alkyl-4-8 membered heterocycloalkyl or _C6 aryloxy; and ^Y2 is unsubstituted or substituted by one or more of linear or branched _C1-6 alkyl, _NH2 , _NMe2 or 5-6 membered heterocycloalkyl.

In more particular embodiments of compounds of formula II, p is 0, 1, 2; Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl; Y ¹ is unsubstituted or substituted with one or more of halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —OC(O)—C _1-4 heteroalkyl, —CHO, —C _1-6 alkylC(O)OH, NH ₂ or C _1-6 alkylhydroxy; and Y ² is hydrogen C ₆ aryl, 5-10 membered heteroaryl, —O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-Ci _-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O)-Ci _-4 alkyl-4-8 membered heterocycloalkyl, and ^Y2 is unsubstituted or substituted with one or more of a linear or branched Ci _-6 alkyl, _NH2 , _NMe2 or a 5-6 membered heterocycloalkyl.

In more particular embodiments of compounds of formula II, p is 0 or 1, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C 1-6 alkyl, —OC(O)—C _1-4 heteroalkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O ₎ O—C _1-6 alkyl, NH ₂ , C _1-6 alkoxy or C _1-6 alkylhydroxy; Y ² is hydrogen, C ₆ aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _{1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-C 1-4 alkyl-} (4-8 membered heterocycloalkyl), -OC(O)-C _1-4 alkyl-4-8 membered heterocycloalkyl or C ₆ aryloxy; and Y ² is unsubstituted or substituted by one or more of linear or branched C _1-6 alkyl, NH ₂ , NMe ₂ or 5-6 membered heterocycloalkyl.

In more particular embodiments of compounds of formula II, n is 1, p is 0, 1, or 2, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or is halogen, preferably F, Cl, or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —OC(O)—C _1-4 heteroalkyl, —C(O)O—C _{1-6 alkyl, —COOH, —CHO, —C 1-6 alkylC} (O)OH, —C _1-6 alkylC(O)O—C and Y2 is unsubstituted or substituted by one or more of linear or branched _C1-6 alkyl, _NH2 , _C1-6 alkoxy or _C1-6 alkylhydroxy; ^Y2 is hydrogen, _C6 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, _C1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O- _C1-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O) _-C1-4 alkyl-4-8 membered heterocycloalkyl or _C6 aryloxy; and ^Y2 is unsubstituted or substituted by one or more of linear or branched _C1-6 alkyl, _NH2 , _NMe2 or 5-6 membered heterocycloalkyl.

In more specific embodiments of compounds of formula II, n is 1, p is 0, 1, 2, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or substituted with one or more of halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —OC(O)—C _1-4 heteroalkyl, —CHO, —C _1-6 alkylC(O)OH, NH ₂ or C _1-6 alkylhydroxy, and Y ² is hydrogen C ₆ aryl, 5-10 membered heteroaryl, —O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-Ci _-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O)-Ci _-4 alkyl-4-8 membered heterocycloalkyl, and ^Y2 is unsubstituted or substituted with one or more of a linear or branched Ci _-6 alkyl, _NH2 , _NMe2 or a 5-6 membered heterocycloalkyl.

In more particular embodiments of compounds of formula II, n is 1, p is 0 or 1, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or is halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF 2 , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC( _O )—C 1-6 alkyl, —OC(O)—C _1-4 heteroalkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, _{—C 1-6 alkylC} (O)OH, —C _1-6 alkylC(O)O—C and Y2 is unsubstituted or substituted by one or more of linear or branched _C1-6 alkyl, _NH2 , _C1-6 alkoxy or _C1-6 alkylhydroxy; ^Y2 is hydrogen, _C6 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, _C1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O- _C1-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O) _-C1-4 alkyl-4-8 membered heterocycloalkyl or _C6 aryloxy; and ^Y2 is unsubstituted or substituted by one or more of linear or branched _C1-6 alkyl, _NH2 , _NMe2 or 5-6 membered heterocycloalkyl.

In more particular embodiments of compounds of formula II, n is 1, p is 0 or 1, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or substituted with one or more of halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —OC(O)—C _1-4 heteroalkyl, —CHO, —C _1-6 alkylC(O)OH, NH ₂ or C _1-6 alkylhydroxy, and Y ² is hydrogen C ₆ aryl, 5-10 membered heteroaryl, —O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-Ci _-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O)-Ci _-4 alkyl-4-8 membered heterocycloalkyl, and ^Y2 is unsubstituted or substituted with one or more of a linear or branched Ci _-6 alkyl, _NH2 , _NMe2 or a 5-6 membered heterocycloalkyl.

In some other particular embodiments of compounds of formula II, R ^a and R ^b are each independently selected from hydrogen, methyl, and ethyl.

In some embodiments of compounds of Formula II, only one R ^a and one R ^b is C _1-4 alkyl, preferably methyl or ethyl, and all other R ^a and R ^b are hydrogen.

In more particular embodiments of compounds of formula II, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or is halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C 1-6 alkyl, —OC(O)—C _1-4 heteroalkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, _{—C 1-6 alkylC} (O)O—C _1-6 alkyl, NH ₂ , C ^{and Y2} is unsubstituted or substituted by one or more of linear or branched _C1-6 alkyl, _{NH2, NMe2, or 5-6 membered heterocycloalkyl ;} and _{R a and R} ^b are each independently selected from ^hydrogen , _methyl ^, _and ethyl.

In more particular embodiments of compounds of formula II, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl; Y ¹ is unsubstituted or substituted with one or more of halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —OC(O)—C _1-4 heteroalkyl, —CHO, —C _1-6 alkylC(O)OH, NH ₂ or C _1-6 alkylhydroxy; and Y ² is hydrogen, C ₆ aryl, 5-10 membered heteroaryl, —O—(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, —O—(4-8 membered heterocycloalkyl), —O—C _1-4 alkyl-(4-8 membered heterocycloalkyl), —OC(O)—C _1-4 alkyl-4-8 membered heterocycloalkyl, Y ² is unsubstituted or substituted with one or more of linear or branched C _1-6 alkyl, NH ₂ , NMe ₂ or 5-6 membered heterocycloalkyl, and each of R ^a and R ^b is independently selected from hydrogen, methyl and ethyl.

In more particular embodiments of compounds of formula II, n is 1, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _{1-6 alkyl, —OC(O)—C 1-4} heteroalkyl, —C(O)O—C 1-6 alkyl, —COOH _, —CHO, _{—C 1-6 alkylC(O)OH, —C 1-6 alkylC (} O)O—C _1-6 alkyl, NH ₂ , C _1-6 alkoxy, or C _1-6 alkylhydroxy; Y ² is hydrogen, C ₆ aryl, 5-10 membered heteroaryl, —O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _{1-4 alkyl 4-8 membered heterocycloalkyl, —O-(4-8 membered heterocycloalkyl), —O—C 1-4 alkyl-} (4-8 membered heterocycloalkyl), —OC(O)—C _1-4 alkyl-4-8 membered heterocycloalkyl, or C ₆ aryloxy; Y ² is unsubstituted or substituted by one or more linear or branched C _1-6 alkyl, NH ₂ , NMe ₂ or 5-6 membered heterocycloalkyl; and each of R ^a and R ^b is independently selected from hydrogen, methyl, and ethyl.

In more particular embodiments of compounds of formula II, n is 1, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or substituted with one or more of halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —OC(O)—C _1-4 heteroalkyl, —CHO, —C _1-6 alkylC(O)OH, NH ₂ or C _1-6 alkylhydroxy, and Y ² is hydrogen C ₆ aryl, 5-10 membered heteroaryl, —O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-Ci _-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O)-Ci _-4 alkyl-4-8 membered heterocycloalkyl; ^Y2 is unsubstituted or substituted with one or more of linear or branched Ci _-6 alkyl, _NH2 , _NMe2 or 5-6 membered heterocycloalkyl; and each of R ^a and R ^b is independently selected from hydrogen, methyl and ethyl.

In more particular embodiments of compounds of formula II, p is 0, 1, 2, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —OC(O)—C _1-4 heteroalkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C ^{and Y2} is unsubstituted or substituted by one or more of linear or branched _C1-6 alkyl, _NH2 , _NMe2 or _5-6 membered heterocycloalkyl; and _{R a and} ^{R b} are _each independently _selected from _hydrogen ^, _{methyl and} ethyl.

In more particular embodiments of compounds of formula II, p is 0, 1, 2; Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl; Y ¹ is unsubstituted or substituted with one or more of halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —OC(O)—C _1-4 heteroalkyl, —CHO, —C _1-6 alkylC(O)OH, NH ₂ or C _1-6 alkylhydroxy; and Y ² is hydrogen C ₆ aryl, 5-10 membered heteroaryl, —O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-Ci _-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O)-Ci _-4 alkyl-4-8 membered heterocycloalkyl; ^Y2 is unsubstituted or substituted with one or more of linear or branched Ci _-6 alkyl, _NH2 , _NMe2 or 5-6 membered heterocycloalkyl; and each of R ^a and R ^b is independently selected from hydrogen, methyl and ethyl.

In more particular embodiments of compounds of formula II, p is 0 or 1, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —OC(O)—C _1-4 heteroalkyl, —C(O)O—C 1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O ₎ O—C _1-6 alkyl, NH ₂ , C _1-6 alkoxy, or C _1-6 alkylhydroxy; Y ² is hydrogen, C ₆ aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _{1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-C 1-4 alkyl-} (4-8 membered heterocycloalkyl), -OC(O)-C _1-4 alkyl-4-8 membered heterocycloalkyl, or C ₆ aryloxy; Y ² is unsubstituted or substituted by one or more linear or branched C _1-6 alkyl, NH ₂ , NMe ₂ , or 5-6 membered heterocycloalkyl; and each of R ^a and R ^b is independently selected from hydrogen, methyl, and ethyl.

In more particular embodiments of compounds of formula II, p is 0 or 1, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or substituted with one or more of halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —OC(O)—C _1-4 heteroalkyl, —CHO, —C _1-6 alkylC(O)OH, NH ₂ or C _1-6 alkylhydroxy, and Y ² is hydrogen C ₆ aryl, 5-10 membered heteroaryl, —O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-Ci _-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O)-Ci _-4 alkyl-4-8 membered heterocycloalkyl; ^Y2 is unsubstituted or substituted with one or more of linear or branched Ci _-6 alkyl, _NH2 , _NMe2 or 5-6 membered heterocycloalkyl; and each of R ^a and R ^b is independently selected from hydrogen, methyl and ethyl.

In more specific embodiments of compounds of formula II, n is 1, p is 0, 1, 2, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —OC(O)—C _1-4 heteroalkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C ^{and Y2} is unsubstituted or substituted by one or more of linear or branched _C1-6 alkyl, _NH2 , _NMe2 or _5-6 membered heterocycloalkyl; and _{R a and} ^{R b} are _each independently _selected from _hydrogen ^, _{methyl and} ethyl.

In more specific embodiments of compounds of formula II, n is 1, p is 0, 1, 2, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or substituted with one or more of halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —OC(O)—C _1-4 heteroalkyl, —CHO, —C _1-6 alkylC(O)OH, NH ₂ or C _1-6 alkylhydroxy, and Y ² is hydrogen C ₆ aryl, 5-10 membered heteroaryl, —O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-Ci _-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O)-Ci _-4 alkyl-4-8 membered heterocycloalkyl; ^Y2 is unsubstituted or substituted with one or more of linear or branched Ci _-6 alkyl, _NH2 , _NMe2 or 5-6 membered heterocycloalkyl; and each of R ^a and R ^b is independently selected from hydrogen, methyl and ethyl.

In more particular embodiments of compounds of formula II, n is 1, p is 0 or 1, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or is halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF 2 , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC( _O )—C 1-6 alkyl, —OC(O)—C _1-4 heteroalkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, _{—C 1-6 alkylC} (O)OH, —C _1-6 alkylC(O)O—C ^{and Y2} is unsubstituted or substituted by one or more of linear or branched _C1-6 alkyl, _NH2 , _NMe2 or _5-6 membered heterocycloalkyl; and _{R a and} ^{R b} are _each independently _selected from _hydrogen ^, _{methyl and} ethyl.

In more particular embodiments of compounds of formula II, n is 1, p is 0 or 1, Y ¹ is hydrogen, C ₆ aryl, 5-10 membered heteroaryl C _3-6 cycloalkyl, Y ¹ is unsubstituted or substituted with one or more of halogen, preferably F, Cl or Br, linear or branched C _1-4 alkyl, linear or branched C _1-6 heteroalkyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —OC(O)—C _1-4 heteroalkyl, —CHO, —C _1-6 alkylC(O)OH, NH ₂ or C _1-6 alkylhydroxy, and Y ² is hydrogen C ₆ aryl, 5-10 membered heteroaryl, —O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-Ci _-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O)-Ci _-4 alkyl-4-8 membered heterocycloalkyl; ^Y2 is unsubstituted or substituted with one or more of linear or branched Ci _-6 alkyl, _NH2 , _NMe2 or 5-6 membered heterocycloalkyl; and each of R ^a and R ^b is independently selected from hydrogen, methyl and ethyl.

In more particular embodiments, the present disclosure is directed to a compound of formula II', or a pharmaceutically acceptable salt or stereoisomer thereof:
(In the formula,
n is 1 or 2;
p is 0, 1, 2, 3, 4, 5, or 6;
Y is hydrogen, _C6 aryl, 5-10 membered heteroaryl, _C3-5 cycloalkyl, Y is unsubstituted or substituted by one or more of linear or branched _C1-4 alkyl, 4-6 membered heterocycloalkyl, _C1-4 alkyl 4-6 membered heterocycloalkyl, _CF3 , _CHF2 , -O-( _CH2 ) ₂ -OMe, _OCF3 , _C1-6 alkylamino, -CN, -N(H)C(O) _-C1-6 alkyl, -OC(O) _-C1-6 alkyl, -C(O)O- _C1-6 alkyl, -COOH, _-C1-6 alkylC(O)OH, _-C1-6 alkylC(O)O- _C1-6 alkyl, _NH2 , _C1-4 alkylhydroxy, _C1-4 alkoxy, halogen, preferably F, Cl, Br;
R ^a and R ^b are each independently selected from hydrogen and straight or branched C _1-4 alkyl, preferably hydrogen and methyl).

In certain embodiments of compounds of Formula II', n is 1.

In more specific embodiments of compounds of Formula II', p is 0, 1, or 2.

In certain embodiments of compounds of Formula II', p is 0 or 1.

In other embodiments of compounds of Formula II', n is 1 and p is 0, 1, or 2.

In certain embodiments of compounds of Formula II', n is 1 and p is 0 or 1.

In some particular embodiments of compounds of formula II', Y is hydrogen, _C6 aryl, 5-10 membered heteroaryl or _C3-5 cycloalkyl, Y is unsubstituted or is selected from linear or branched _C1-4 alkyl, 4-6 membered heterocycloalkyl, _{C1-4 alkyl 4-6} membered heterocycloalkyl, _CF3 , _CHF2 , -O-( _CH2 ) ₂ -OMe, _OCF3 , _C1-6 alkylamino, -CN, -N(H)C(O)-C1-6 alkyl, -OC(O) _{-C1-6 alkyl, -C(O)O-C1-6 alkyl} , -COOH, _-C1-6 alkylC(O)OH, _-C1-6 alkylC(O) _{O-C1-6 alkyl} , _NH2 , _C1-4 alkylhydroxy, C It is substituted with one or more of _{1 to 4} alkoxy, halogen, preferably F, Cl, Br.

In some particular embodiments of compounds of formula II', Y is hydrogen, _C6 aryl, 5-10 membered heteroaryl or _C3-5 cycloalkyl, Y is unsubstituted or is selected from the group consisting of straight chained or branched _C1-4 alkyl, morpholinyl, -( _CH2 )-morpholinyl, piperazinyl, -( _CH2 )-piperazinyl, _CF3 , _CHF2 , -O-( _CH2 ) ₂ -OMe, OCF3, _C1-6 alkylamino, -CN, -N(H)C ₍ O)-C1-6 alkyl, -OC(O) _-C1-6 alkyl, -C(O)O- _C1-6 alkyl, -COOH, _-C1-6 alkylC(O)OH, _-C1-6 alkylC( _O )O- _C1-6 alkyl, _NH2 , _C1-4 alkylhydroxy, C It is substituted with one or more of _{1 to 4} alkoxy, halogen, preferably F, Cl, Br.

In still other specific embodiments of compounds of formula II', Y is hydrogen, _C6 aryl, or _C3-5 cycloalkyl, and Y is unsubstituted or is selected from the group consisting of linear or branched _C1-4 alkyl, 4-6 membered heterocycloalkyl, _C1-4 alkyl 4-6 membered heterocycloalkyl, _CF3 , _CHF2 , -O-( _CH2 ) _2- OMe, _OCF3 , _{C1-6 alkylamino, -CN, -N(H)C(O)-C1-6 alkyl} , -OC(O) _{-C1-6 alkyl, -C(O)O-C1-6 alkyl} , -COOH, _-C1-6 alkylC(O)OH, _-C1-6 alkylC(O)O- _C1-6 alkyl, _NH2 , _C1-4 alkylhydroxy, C1-4 ... It is substituted with one or more of _{1 to 4} alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl.

In still other specific embodiments of compounds of formula II', Y is hydrogen, _C6 aryl, or _C3-5 cycloalkyl, and Y is unsubstituted or a linear or branched _C1-4 alkyl, morpholinyl, -( _CH2 )-morpholinyl, piperazinyl, -( _CH2 )-piperazinyl, _CF3 , _CHF2 , -O-( _CH2 ) _2- OMe, OCF3, _C1-6 alkylamino, -CN, -N(H)C(O) _-C1-6 alkyl, -OC(O) _-C1-6 alkyl, -C(O)O- _C1-6 alkyl, -COOH, _{-C1-6 alkylC} (O)OH, _-C1-6 alkylC(O)O- _C1-6 alkyl, _NH2 , _C1-4 alkylhydroxy, C It is substituted with one or more of _{1 to 4} alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl.

In still other particular embodiments of compounds of formula II', Y is hydrogen, _C6 aryl, or _C3-5 cycloalkyl, and Y is unsubstituted or substituted with one or more of linear or branched _C1-4 alkyl, _CF3 , _OCF3 , _C1-4 alkylamino, -CN, _C1-4 alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl.

In more particular embodiments of compounds of formula II', n is 1 and Y is hydrogen, C ₆ aryl or C _3-5 cycloalkyl, and Y is unsubstituted or a linear or branched C _1-4 alkyl, 4-6 membered heterocycloalkyl, C _1-4 alkyl 4-6 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C 1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _{1-4 alkylhydroxy} , C It is substituted with one or more of _{1 to 4} alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl.

In more particular embodiments of compounds of formula II', n is 1 and Y is hydrogen, _C6 aryl or _C3-5 cycloalkyl, and Y is unsubstituted or substituted with one or more of linear or branched _C1-4 alkyl, _CF3 , _OCF3 , _C1-4 alkylamino, -CN, _C1-4 alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl.

In still further specific embodiments of compounds of formula II', p is 0, 1, or 2, Y is hydrogen, C ₆ aryl, or C _3-5 cycloalkyl, and Y is unsubstituted or a linear or branched C _1-4 alkyl, 4-6 membered heterocycloalkyl, C _1-4 alkyl 4-6 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C 1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _{1-4 alkylhydroxy} , C It is substituted with one or more of _{1 to 4} alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl.

In still further specific embodiments of compounds of formula II', p is 0, 1, or 2, and Y is hydrogen, _C6 aryl, or _C3-5 cycloalkyl, and Y is unsubstituted or substituted with one or more of linear or branched _C1-4 alkyl, _CF3 , _OCF3 , _C1-4 alkylamino, -CN, _C1-4 alkoxy, halogen, preferably F, Cl, Br, and more preferably F or Cl.

In still further specific embodiments of compounds of formula II', p is 0 or 1, Y is hydrogen, C ₆ aryl, or C _3-5 cycloalkyl, and Y is unsubstituted or a linear or branched C _1-4 alkyl, 4-6 membered heterocycloalkyl, C _1-4 alkyl 4-6 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C 1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _{1-4 alkylhydroxy} , C It is substituted with one or more of _{1 to 4} alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl.

In still further particular embodiments of compounds of formula II', p is 0 or 1, Y is hydrogen, _C6 aryl, or _C3-5 cycloalkyl, and Y is unsubstituted or substituted with one or more of linear or branched _C1-4 alkyl, _CF3 , _OCF3 , _C1-4 alkylamino, -CN, _C1-4 alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl.

In even more particular embodiments of compounds of formula II', n is 1, p is 0, 1, or 2, and Y is unsubstituted or substituted with one or more of linear or branched C _1-4 alkyl, 4- to 6-membered heterocycloalkyl, C _1-4 alkyl 4- to 6-membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-4 alkylhydroxy, C _1-4 alkoxy, halogen, preferably F, Cl, Br, and more preferably F or Cl.

In even more particular embodiments of compounds of formula II', n is 1, p is 0, 1, or 2, and Y is unsubstituted or substituted with one or more of linear or branched C _1-4 alkyl, CF ₃ , OCF ₃ , C _1-4 alkylamino, —CN, C _1-4 alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl.

In even more particular embodiments of compounds of formula II', n is 1, p is 0 or 1, and Y is unsubstituted or substituted with one or more of linear or branched C _1-4 alkyl, 4- to 6-membered heterocycloalkyl, C _1-4 alkyl 4- to 6-membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-4 alkylhydroxy, C _1-4 alkoxy, halogen, preferably F, Cl, Br, and more preferably F or Cl.

In even more particular embodiments of compounds of formula II', n is 1, p is 0 or 1, and Y is unsubstituted or substituted with one or more of linear or branched C _1-4 alkyl, CF ₃ , OCF ₃ , C _1-4 alkylamino, —CN, C _1-4 alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl.

In some other particular embodiments of compounds of formula II', R ^{1 a} and R 1 ^b are each independently selected from hydrogen, methyl and ethyl, preferably hydrogen and methyl.

In some embodiments of compounds of Formula II', only one R ^a and one R ^b is C _1-4 alkyl, preferably methyl, and all other R ^a and R ^b are hydrogen.

In still other specific embodiments of compounds of formula II', Y is hydrogen, _C6 aryl, _C3-5 cycloalkyl, Y is unsubstituted or is selected from the group consisting of linear or branched _C1-4 alkyl, 4-6 membered heterocycloalkyl, _C1-4 alkyl 4-6 membered heterocycloalkyl, _CF3 , _CHF2 , -O-( _CH2 ) _2- OMe, _{OCF3, C1-6 alkylamino, -CN, -N(H)C(O)-C1-6 alkyl, -OC(O} ) _{-C1-6 alkyl, -C(O)O-C1-6 alkyl} , -COOH, _-C1-6 alkylC(O)OH, _-C1-6 alkylC(O)O _{- C1-6} alkyl, _NH2 , _C1-4 alkylhydroxy, C It is substituted with one or more of _{1 to 4} alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and each of R ^a and R ^b is independently selected from hydrogen, methyl and ethyl.

In still other specific embodiments of compounds of formula II', Y is hydrogen, _C6 aryl, _C3-5 cycloalkyl; Y is unsubstituted or substituted with one or more of linear or branched _C1-4 alkyl, _CF3 , _OCF3 , _C1-4 alkylamino, -CN, _C1-4 alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl; and each of R ^a and R ^b is independently selected from hydrogen, methyl, and ethyl.

In more particular embodiments of compounds of formula II', n is 1 and Y is hydrogen, C ₆ aryl, C _3-5 cycloalkyl, and Y is unsubstituted or a linear or branched C _1-4 alkyl, 4-6 membered heterocycloalkyl, C _1-4 alkyl 4-6 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C 1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _{1-4 alkylhydroxy} , C substituted with one or more of _{1 to 4} alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl; and each of R ^a and R ^b is independently selected from hydrogen, methyl and ethyl.

In more particular embodiments of compounds of formula II', n is 1, Y is hydrogen, _C6 aryl, _C3-5 cycloalkyl, Y is unsubstituted or substituted with one or more of linear or branched _C1-4 alkyl, _CF3 , _OCF3 , _C1-4 alkylamino, -CN, _C1-4 alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and each of R ^a and R ^b is independently selected from hydrogen, methyl and ethyl.

In still further specific embodiments of compounds of formula II', p is 0, 1, or 2; Y is hydrogen, C ₆ aryl, C _3-5 cycloalkyl; Y is unsubstituted or a linear or branched C _1-4 alkyl, 4-6 membered heterocycloalkyl, C _1-4 alkyl 4-6 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C 1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-4 alkylhydroxy _, C substituted with one or more of _{1 to 4} alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl; and each of R ^a and R ^b is independently selected from hydrogen, methyl and ethyl.

In still further specific embodiments of compounds of formula II', p is 0, 1, or 2; Y is hydrogen, _C6 aryl, _C3-5 cycloalkyl; Y is unsubstituted or substituted with one or more of linear or branched _C1-4 alkyl, _CF3 , _OCF3 , _C1-4 alkylamino, -CN, _C1-4 alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl; and each of R ^a and R ^b is independently selected from hydrogen, methyl, and ethyl.

In still further specific embodiments of compounds of formula II', p is 0 or 1, Y is hydrogen, C ₆ aryl, C _3-5 cycloalkyl, Y is unsubstituted or is selected from the group consisting of linear or branched C _1-4 alkyl, 4-6 membered heterocycloalkyl, C _1-4 alkyl 4-6 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _{1-6 alkyl, —COOH, —C 1-6 alkylC} (O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-4 alkylhydroxy, C substituted with one or more of _{1 to 4} alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl; and each of R ^a and R ^b is independently selected from hydrogen, methyl and ethyl.

In still further specific embodiments of compounds of formula II', p is 0 or 1, Y is hydrogen, _C6 aryl, _C3-5 cycloalkyl, Y is unsubstituted or substituted with one or more of linear or branched _C1-4 alkyl, _CF3 , _OCF3 , _C1-4 alkylamino, -CN, _C1-4 alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and each of R ^a and R ^b is independently selected from hydrogen, methyl and ethyl.

In even more particular embodiments of compounds of formula II', n is 1, p is 0, 1, or 2, Y is unsubstituted or substituted with one or more of linear or branched C _1-4 alkyl, 4-6 membered heterocycloalkyl, C _1-4 alkyl 4-6 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-4 alkylhydroxy, C _1-4 alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl; and R Each of ^a and R ^b is independently selected from hydrogen, methyl and ethyl.

In even more particular embodiments of compounds of formula II', n is 1, p is 0, 1, or 2, Y is unsubstituted or substituted with one or more of linear or branched C _1-4 alkyl, CF ₃ , OCF ₃ , C _1-4 alkylamino, —CN, C _1-4 alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and each of R ^a and R ^b is independently selected from hydrogen, methyl, and ethyl.

In even more particular embodiments of compounds of formula II', n is 1, p is 0 or 1, Y is unsubstituted or substituted with one or more of linear or branched C _1-4 alkyl, 4-6 membered heterocycloalkyl, C _1-4 alkyl 4-6 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-4 alkylhydroxy, C _1-4 alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl; and R Each of ^a and R ^b is independently selected from hydrogen, methyl and ethyl.

In even more particular embodiments of compounds of formula II', n is 1, p is 0 or 1, Y is unsubstituted or substituted with one or more of linear or branched C _1-4 alkyl, CF ₃ , OCF ₃ , C _1-4 alkylamino, —CN, C _1-4 alkoxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and each of R ^a and R ^b is independently selected from hydrogen, methyl and ethyl.

More particularly, the present disclosure is directed to compounds of formula IIIa, IIIb, or IIIc, or pharmaceutically acceptable salts or stereoisomers thereof:
(In the formula,
n is 1 or 2;
p is 0, 1 or 2;
one of w ¹ , w ² or w ³ is selected from C and N, and the other two of w ¹ , w ² or w ³ are C;
one or two of w ⁴ , w ⁵ , w ⁶ , w ⁷ are selected from C, O, N, NMe, NH or S, while two or three of w ⁴ , w ⁵ , w ⁶ and w ⁷ are C;
R ¹ , R ² , R ³ and R ⁴ are each hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ —O—(CH ₂ ) ₂ —OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C are independently selected from _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R ¹ , R ² , R ³ , R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl;
R ⁵ and R ⁶ are each independently selected from hydrogen, linear or branched C _1-4 alkyl, CF ₃ , CHF ₂ , halogen, preferably F, Cl, Br, more preferably F or Cl;
^X3 is absent, hydrogen, or 4- to 8-membered heterocycloalkyl, _C1-4 alkyl 4- to 8-membered heterocycloalkyl, -O-(4- to 8-membered heterocycloalkyl), _-C1-4 alkoxy-(4- to 8-membered heterocycloalkyl), 5- to 10-membered heteroaryl, -O-(5- to 10-membered heteroaryl), -OC(O)-C1-4 alkyl- _4- to 8-membered heterocycloalkyl, wherein ^X3 is unsubstituted or substituted with one or more of a linear or branched _C1-6 alkyl, _NH2 , _NMe2 , or 5- to 6-membered heterocycloalkyl;
Z is a straight or branched chain C _1-6 alkyl, or C _3-6 cycloalkyl, C _1-4 alkoxy or C _1-4 alkyl-C _1-4 alkoxy, and Z is unsubstituted or substituted by C _1-4 alkyl.

More particularly, the present disclosure is directed to a compound of formula IIIa, or a pharmaceutically acceptable salt or stereoisomer thereof:
(In the formula,
n is 1 or 2;
p is 0, 1 or 2;
one of w ¹ , w ² or w ³ is selected from C and N, and the other two of w ¹ , w ² or w ³ are C;
R ¹ , R ² , R ³ and R ⁴ are each hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ —O—(CH ₂ ) ₂ —OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C are independently selected from _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R ¹ , R ² , R ³ , R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl;
^X3 is absent, hydrogen, or 4-8 membered heterocycloalkyl, _C1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), _-C1-4 alkoxy-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), -OC(O) _-C1-4 alkyl-4-8 membered heterocycloalkyl, and ^X3 is unsubstituted or substituted with one or more of a linear or branched _C1-6 alkyl, _NH2 , _NMe2 , or 5-6 membered heterocycloalkyl.

More particularly, the present disclosure is directed to a compound of formula IIIb, or a pharmaceutically acceptable salt or stereoisomer thereof:
(In the formula,
n is 1 or 2;
p is 0, 1 or 2;
Z is a straight or branched chain C _1-6 alkyl, or C _3-6 cycloalkyl, C _1-4 alkoxy or C _1-4 alkyl-C _1-4 alkoxy, and Z is unsubstituted or substituted by C _1-4 alkyl.

More particularly, the present disclosure is directed to a compound of formula IIIc, or a pharmaceutically acceptable salt or stereoisomer thereof:
(In the formula,
n is 1 or 2;
p is 0, 1 or 2;
one of w ¹ , w ² or w ³ is selected from C and N, and the other two of w ¹ , w ² or w ³ are C;
one or two of w ⁴ , w ⁵ , w ⁶ , w ⁷ are selected from C, O, N, NMe, NH or S, while two or three of w ⁴ , w ⁵ , w ⁶ and w ⁷ are C;
R ¹ , R ² , R ³ and R ⁴ are each hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ —O—(CH ₂ ) ₂ —OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C are independently selected from _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R ¹ , R ² , R ³ , R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl;
R ⁵ and R ⁶ are each independently selected from hydrogen, linear or branched C _1-4 alkyl, CF ₃ , CHF ₂ , halogen, preferably F, Cl, Br, more preferably F or Cl;
^X3 is absent, hydrogen, or 4- to 8-membered heterocycloalkyl, _C1-4 alkyl 4- to 8-membered heterocycloalkyl, -O-(4- to 8-membered heterocycloalkyl), _-C1-4 alkoxy-(4- to 8-membered heterocycloalkyl), 5- to 10-membered heteroaryl, -O-(5- to 10-membered heteroaryl), -OC(O)-C1-4 alkyl- _4- to 8-membered heterocycloalkyl, wherein ^X3 is unsubstituted or substituted with one or more of a linear or branched _C1-6 alkyl, _NH2 , _NMe2 , or 5- to 6-membered heterocycloalkyl;
Z is a straight or branched chain C _1-6 alkyl, or C _3-6 cycloalkyl, C _1-4 alkoxy or C _1-4 alkyl-C _1-4 alkoxy, and Z is unsubstituted or substituted by C _1-4 alkyl.

In some embodiments of compounds of Formula IIIa, IIIb, or IIIc, or pharmaceutically acceptable salts or stereoisomers thereof, n is 1.

In certain embodiments of a compound of Formula IIIa, IIIb, or IIIc, or a pharmaceutically acceptable salt or stereoisomer thereof, p is 0 or 1.

In some embodiments of a compound of Formula IIIa, IIIb, or IIIc, or a pharmaceutically acceptable salt or stereoisomer thereof, p is 0.

In other embodiments of the compound of Formula IIIa, IIIb, or IIIc, or a pharmaceutically acceptable salt or stereoisomer thereof, p is 1.

In some embodiments of a compound of Formula IIIa, IIIb, or IIIc, or a pharmaceutically acceptable salt or stereoisomer thereof, n is 1 and p is 0 or 1.

In some embodiments of a compound of Formula IIIa, IIIb, or IIIc, or a pharmaceutically acceptable salt or stereoisomer thereof, n is 1 and p is 0.

In some embodiments of the compound of Formula IIIa, or a pharmaceutically acceptable salt or stereoisomer thereof, R ¹ , R ² , and R ³ are defined as above, and R ⁴ is hydrogen, wherein the aromatic ring contains four or five substituents that are not hydrogen.

In some embodiments of the compound of Formula IIIa, or a pharmaceutically acceptable salt or stereoisomer thereof, ^R1 and ^R2 are defined as above, and ^R3 and ^R4 are each hydrogen, wherein the aromatic ring contains three or four substituents that are not hydrogen.

In specific compounds of IIIa, IIIb or IIIc, R ¹ , R ² , R ³ and R ⁴ are each independently selected from hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —CHO, —C _1-6 alkylC(O)OH, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R ¹ , R ² , R ³ , R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl, R ⁵ , R ⁶ are each independently selected from hydrogen, linear or branched C _1-4 alkyl and CF ₃ ; ³ is absent, hydrogen or 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, —O—(4-8 membered heterocycloalkyl), —C _1-4 alkoxy-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, —O—(5-10 membered heteroaryl), —OC(O)—C _1-4 alkyl-4-8 membered heterocycloalkyl, and X ³ is unsubstituted or substituted with one or more of a linear or branched C _1-6 alkyl, NH ₂ , NMe ₂ or 5-6 membered heterocycloalkyl.

In some embodiments of compounds of Formula IIIa, IIIb, or IIIc, n is 1 and R ¹ , R ² , R ³ , R ⁴ are each hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ —O—(CH ₂ ) ₂ —OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C and/or two of R ¹ , R ² , R ³ , R 4 together form a _5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl, R ⁵ and R ⁶ are each independently selected from hydrogen, linear or branched C _1-4 alkyl, CF ₃ , CHF ₂ , halogen, preferably F, Cl, Br, more preferably F or Cl, X ³ is absent, hydrogen or ^a 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, —O—(4-8 membered heterocycloalkyl), —C _1-4 alkoxy-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, —O—(5-10 membered heteroaryl), —OC(O)—C _1-4 alkyl-4-8 membered heterocycloalkyl, ³ is unsubstituted or substituted with one or more of straight or branched chain C _1-6 alkyl, NH ₂ , NMe ₂ or 5-6 membered heterocycloalkyl.

In specific compounds of IIIa, IIIb or IIIc, n is 1 and R ¹ , R ² , R ³ and R ⁴ are each independently selected from hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —CHO, —C _1-6 alkylC(O)OH, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl; and/or two of R ¹ , R ² , R ³ and R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl, and R ⁵ and R ⁶ are each hydrogen, linear or branched C _1-4 alkyl and CF ₃ , where X ³ is absent, hydrogen, or 4- to 8-membered heterocycloalkyl, C _1-4 alkyl 4- to 8-membered heterocycloalkyl, —O—(4- to 8-membered heterocycloalkyl), —C _1-4 alkoxy-(4- to 8-membered heterocycloalkyl), 5- to 10-membered heteroaryl, —O—(5- to 10-membered heteroaryl), —OC(O)—C _1-4 alkyl-4- to 8-membered heterocycloalkyl, and X ³ is unsubstituted or substituted with one or more of a linear or branched C _1-6 alkyl, NH ₂ , NMe ₂ , or 5- to 6-membered heterocycloalkyl.

In some embodiments of compounds of Formula IIIa, IIIb, or IIIc, p is 0, 1, or 2; and R ¹ , R ² , R ³ , and R ⁴ are each hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ —O—(CH ₂ ) ₂ —OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C and/or two of R ¹ , R ² , R ³ , R 4 together form a _5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl, R ⁵ and R ⁶ are each independently selected from hydrogen, linear or branched C _1-4 alkyl, CF ₃ , CHF ₂ , halogen, preferably F, Cl, Br, more preferably F or Cl, X ³ is absent, hydrogen or ^a 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, —O—(4-8 membered heterocycloalkyl), —C _1-4 alkoxy-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, —O—(5-10 membered heteroaryl), —OC(O)—C _1-4 alkyl-4-8 membered heterocycloalkyl, ³ is unsubstituted or substituted with one or more of straight or branched chain C _1-6 alkyl, NH ₂ , NMe ₂ or 5-6 membered heterocycloalkyl.

In specific compounds of IIIa, IIIb or IIIc, p is 0, 1 or 2; R ¹ , R ² , R ³ and R ⁴ are each independently selected from hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —CHO, —C _1-6 alkylC(O)OH, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl; and/or two of R ¹ , R ² , R ³ and R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl; R ⁵ and R ⁶ are each independently selected from hydrogen, linear or branched C _1-4 alkyl and CF ₃ , where X ³ is absent, hydrogen, or 4- to 8-membered heterocycloalkyl, C _1-4 alkyl 4- to 8-membered heterocycloalkyl, —O—(4- to 8-membered heterocycloalkyl), —C _1-4 alkoxy-(4- to 8-membered heterocycloalkyl), 5- to 10-membered heteroaryl, —O—(5- to 10-membered heteroaryl), —OC(O)—C _1-4 alkyl-4- to 8-membered heterocycloalkyl, and X ³ is unsubstituted or substituted with one or more of a linear or branched C _1-6 alkyl, NH ₂ , NMe ₂ , or 5- to 6-membered heterocycloalkyl.

In some embodiments of compounds of Formula IIIa, IIIb, or IIIc, p is 0 or 1 and R ¹ , R ² , R ³ , R ⁴ are each hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ —O—(CH ₂ ) ₂ —OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —OC(O)—C _1-6 alkyl, —C(O)O—C _{1-6 alkyl, —COOH, —CHO, —C 1-6 alkylC} (O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C and/or two of R ¹ , R ² , R ³ , R 4 together form a _5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl, R ⁵ and R ⁶ are each independently selected from hydrogen, linear or branched C _1-4 alkyl, CF ₃ , CHF ₂ , halogen, preferably F, Cl, Br, more preferably F or Cl, X ³ is absent, hydrogen or ^a 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, —O—(4-8 membered heterocycloalkyl), —C _1-4 alkoxy-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, —O—(5-10 membered heteroaryl), —OC(O)—C _1-4 alkyl-4-8 membered heterocycloalkyl, ³ is unsubstituted or substituted with one or more of straight or branched chain C _1-6 alkyl, NH ₂ , NMe ₂ or 5-6 membered heterocycloalkyl.

In specific compounds of IIIa, IIIb or IIIc, p is 0 or 1; R ¹ , R ² , R ³ and R ⁴ are each independently selected from hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —CHO, —C _1-6 alkylC(O)OH, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl; and/or two of R ¹ , R ² , R ³ and R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl; R ⁵ and R ⁶ are each independently selected from hydrogen, linear or branched C _1-4 alkyl and CF ₃ , where X ³ is absent, hydrogen, or 4- to 8-membered heterocycloalkyl, C _1-4 alkyl 4- to 8-membered heterocycloalkyl, —O—(4- to 8-membered heterocycloalkyl), —C _1-4 alkoxy-(4- to 8-membered heterocycloalkyl), 5- to 10-membered heteroaryl, —O—(5- to 10-membered heteroaryl), —OC(O)—C _1-4 alkyl-4- to 8-membered heterocycloalkyl, and X ³ is unsubstituted or substituted with one or more of a linear or branched C _1-6 alkyl, NH ₂ , NMe ₂ , or 5- to 6-membered heterocycloalkyl.

In some embodiments of compounds of Formula IIIa, IIIb, or IIIc, n is 1, p is 0, 1, or 2, and R ¹ , R ² , R ³ , and R ⁴ are each hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ —O—(CH ₂ ) ₂ —OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH and/or two of R ¹ , R 2 , R ³ , R ₄ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl, R ⁵ and R ⁶ are each independently selected from hydrogen, linear or branched C _1-4 alkyl, CF ₃ , CHF ₂ , halogen, preferably F, Cl, Br, more preferably F or Cl, ^{X 3 is} absent, hydrogen or a 4-8 membered heterocycloalkyl, C ^1-4 alkyl _4-8 membered heterocycloalkyl, —O— ₍ 4-8 membered heterocycloalkyl), —C _1-4 alkoxy-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, —O—(5-10 membered heteroaryl), —OC(O)—C _1-4 alkyl-4-8 membered heterocycloalkyl, and X ³ is unsubstituted or substituted with one or more of straight or branched chain C _1-6 alkyl, NH ₂ , NMe ₂ or 5-6 membered heterocycloalkyl.

In specific compounds of IIIa, IIIb or IIIc, n is 1, p is 0, 1 or 2, R ¹ , R ² , R ³ and R ⁴ are each independently selected from hydrogen, linear or branched C _1-6 alkyl, linear or branched C 1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF _{2 , OCF 3 ,} —CN, —CHO, —C _1-6 alkylC(O)OH, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R 1 , R 2 , R 3 , R 4 together form a _{5-6 membered heterocycloalkyl or a 5-6} membered heteroaryl, and R 5 , R 6 are each hydrogen, linear or branched C 1-6 heteroalkyl, C 6 aryl, preferably phenyl, CF ³ , CHF ² , —O—CHF ² , OCF ³ , —CN, —CHO, —C 1-6 alkylC(O)OH, NH ² , C 1-4 alkylhydroxy, halogen, preferably F, Cl, ^Br , more preferably F or Cl; and _CF3 , where ^X3 is absent, hydrogen, or 4-8 membered heterocycloalkyl, _C1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), _-C1-4 alkoxy-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), -OC(O _{)-C1-4 alkyl} -4-8 membered heterocycloalkyl, and ^X3 is unsubstituted or substituted with one or more of linear or branched _C1-6 alkyl, _NH2 , _NMe2 , or 5-6 membered heterocycloalkyl.

In some embodiments of compounds of Formula IIIa, IIIb, or IIIc, n is 1, p is 0 or 1, and R ¹ , R ² , R ³ , and R ⁴ are each hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ —O—(CH ₂ ) ₂ —OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R ¹ , R ² , R ³ , R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl, R ⁵ and R ⁶ are each independently selected from hydrogen, linear or branched C _1-4 alkyl, CF ₃ , CHF ₂ , halogen, preferably F, Cl, Br, more preferably F or Cl, X ³ is absent, hydrogen or a 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, —O-(4-8 membered heterocycloalkyl), —C _1-4 alkoxy-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, —O-(5-10 membered heteroaryl), —OC(O)—C _1-4 alkyl-4-8 membered heterocycloalkyl, ³ is unsubstituted or substituted with one or more of a straight or branched chain C _1-6 alkyl, NH ₂ , NMe ₂ or 5-6 membered heterocycloalkyl.

In specific compounds of IIIa, IIIb or IIIc, n is 1, p is 0 or 1, R ¹ , R ² , R ³ and R ⁴ are each independently selected from hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF 3 , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —CHO, —C 1-6 alkylC(O)OH, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R ₁ , R 2 , R 3 , R 4 together form a _5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl, and R ⁵ , R ⁶ are each hydrogen, linear or branched C 1-6 heteroalkyl, C 6 aryl, preferably phenyl, CF ³ , CHF 2 , —O—CHF 2 , OCF ³ , —CN, —CHO, —C 1-6 alkylC(O)OH, NH ² , C ^1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl; and _CF3 , where ^X3 is absent, hydrogen, or 4-8 membered heterocycloalkyl, _C1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), _-C1-4 alkoxy-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), -OC(O _{)-C1-4 alkyl} -4-8 membered heterocycloalkyl, and ^X3 is unsubstituted or substituted with one or more of linear or branched _C1-6 alkyl, _NH2 , _NMe2 , or 5-6 membered heterocycloalkyl.

In some embodiments of compounds of Formula IIIb, C _1-6 alkyl is chosen from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, iso-hexyl, and neohexyl.

In some embodiments of the compound of Formula IIIb, the C _3-6 cycloalkyl is chosen from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In some embodiments of compounds of Formula IIIb, the C _1-4 alkoxy is selected from methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, and t-butoxy.

In some embodiments of compounds of Formula IIIb, " _{Ci_4} alkyl- _{Ci_4} alkoxy" is selected from methyl-methoxy, methyl-ethoxy, methyl-n-propoxy, methyl-iso-propoxy, methyl-n-butoxy, methyl-iso-butoxy, methyl-t-butoxy, ethyl-methoxy, ethyl-ethoxy, ethyl-n-propoxy, ethyl-iso-propoxy, ethyl-n-butoxy, ethyl-iso-butoxy, ethyl-t-butoxy, propyl-methoxy, propyl-ethoxy, propyl-n-propoxy, propyl-iso-propoxy, propyl-n-butoxy, propyl-iso-butoxy, and propyl-t-butoxy.

In certain embodiments of compounds of Formula IIIb, Z is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or t-butoxy, and Z is unsubstituted or substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl.

In certain embodiments of compounds of Formula IIIb, Z is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or t-butoxy.

In more specific embodiments of compounds of Formula IIIb, Z is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or t-butoxy, and Z is unsubstituted or substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl; and n is 1.

In certain embodiments of compounds of Formula IIIb, Z is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or t-butoxy, and n is 1.

In more specific embodiments of compounds of Formula IIIb, Z is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, Z is unsubstituted or substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and p is 0, 1, or 2.

In more specific embodiments of compounds of Formula IIIb, Z is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, Z is unsubstituted or substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl, and p is 0 or 1.

In still further specific embodiments of compounds of Formula IIIb, Z is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, Z is unsubstituted or substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n isobutyl, t-butyl, n is 1, and p is 0, 1, or 2.

In still further specific embodiments of compounds of Formula IIIb, Z is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, Z is unsubstituted or substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n isobutyl, t-butyl, n is 1, and p is 0 or 1.

In a more particular embodiment, the present disclosure is directed to a compound of formula IIIa-1, or a pharmaceutically acceptable salt or stereoisomer thereof:
(In the formula,
one of w ¹ , w ² or w ³ is selected from C and N, and the other two of w ¹ , w ² or w ³ are C;
R ¹ , R ² , R ³ and R ⁴ are each hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ —O—(CH ₂ ) ₂ —OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C independently selected from _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R ¹ , R ² , R ³ , R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl;
^X3 is absent, hydrogen, or 4-8 membered heterocycloalkyl, _C1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), _-C1-4 alkoxy-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), -OC(O) _-C1-4 alkyl-4-8 membered heterocycloalkyl, and ^X3 is unsubstituted or substituted with one or more of a linear or branched _C1-6 alkyl, _NH2 , _NMe2 , or 5-6 membered heterocycloalkyl.

In specific compounds of IIIa-1, R ¹ , R ² , R ³ and R ⁴ are each independently selected from hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —CHO, —C _1-6 alkylC(O)OH, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R ¹ , R ² , R ³ , R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl, and X ³ is absent, hydrogen or _{a 4-8 membered heterocycloalkyl, C 1-4} alkyl 4-8 membered heterocycloalkyl, —O—(4-8 membered heterocycloalkyl), —C _1-4 alkoxy-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, —O—(5-10 membered heteroaryl), —OC(O)—C _1-4 alkyl-4-8 membered heterocycloalkyl, and X ³ is unsubstituted or substituted with one or more of a straight or branched C _1-6 alkyl, NH ₂ , NMe ₂ or 5-6 membered heterocycloalkyl.

In some embodiments of the compounds of Formula IIIa-1, or pharmaceutically acceptable salts or stereoisomers thereof, R ¹ , R ² , and R ³ are defined as above, and R ⁴ is hydrogen, where the aromatic ring contains four or five substituents that are not hydrogen.

In some embodiments of the compounds of Formula IIIa-1, or pharmaceutically acceptable salts or stereoisomers thereof, R ¹ and R ² are defined as above, and R ³ and R ⁴ are each hydrogen, where the aromatic ring contains three or four substituents that are not hydrogen.

In more specific embodiments, the present disclosure is directed to compounds of formula IIIa-2, IIIa-3, IIIa-4, or IIIa-5, or pharmaceutically acceptable salts or stereoisomers thereof:
(In the formula,
R ¹ , R ² , R ³ and R ⁴ are each hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ —O—(CH ₂ ) ₂ —OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C independently selected from _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R ¹ , R ² , R ³ , R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl;
^X3 is absent, hydrogen, or 4-8 membered heterocycloalkyl, _C1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), _-C1-4 alkoxy-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), -OC(O) _-C1-4 alkyl-4-8 membered heterocycloalkyl, and ^X3 is unsubstituted or substituted with one or more of a linear or branched _C1-6 alkyl, _NH2 , _NMe2 , or 5-6 membered heterocycloalkyl.

In specific compounds of formula IIIa-2, IIIa-3, IIIa-4 or IIIa-5, R ¹ , R ² , R ³ and R ⁴ are each independently selected from hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —CHO, —C _1-6 alkylC(O)OH, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R ¹ , R ² , R ³ , R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl, and X ³ is absent, hydrogen or a 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, —O—(4-8 membered heterocycloalkyl), —C _1-4 alkoxy-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, —O—(5-10 membered heteroaryl), —OC(O)—C _1-4 alkyl-4-8 membered heterocycloalkyl, and X ³ is unsubstituted or substituted with one or more of a linear or branched C _1-6 alkyl, NH ₂ , NMe ₂ or 5-6 membered heterocycloalkyl.

In still further specific embodiments of Formula IIIa-2, R ¹ , R ² , R ³ and R ⁴ are each independently selected from hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —CHO, —C _1-6 alkylC(O)OH, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R ¹ , R ² , R ³ , R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl, and X ³ is absent, hydrogen or a 4-8 membered heterocycloalkyl, C and X3 is unsubstituted or substituted with one or more of linear or branched C1-6 alkyl, NH2, NMe2, or 5-6 membered heterocycloalkyl; while in compounds of formula _{IIIa-3 ,} ^IIIa - ₄ , or IIIa-5, ^R1 and _R2 are each independently selected from hydrogen, _linear or branched _C1-6 alkyl, and halogen, preferably Cl _; while ^{R3 and R4} are hydrogen.

In more particular embodiments, the compound of formula IIIa, IIIa-1, IIIa-2, IIIa-3, IIIa-4, or IIIa-5 is given by a compound of formula IIIa-2a, IIIa-2b, IIIa-2c, IIIa-3a, IIIa-4a, or IIIa-5a, or a pharmaceutically acceptable salt or stereoisomer thereof:
(In the formula,
R ¹ , R ² , R ³ and R ⁴ are each hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ —O—(CH ₂ ) ₂ —OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C independently selected from _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R ¹ , R ² , R ³ , R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl;
^X3 is hydrogen or 4-8 membered heterocycloalkyl, _{C1-4 alkyl 4-8} membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), _{-C1-4 alkoxy-(4-8} membered heterocycloalkyl), 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), -OC(O) _-C1-4 alkyl-4-8 membered heterocycloalkyl, where ^X3 is unsubstituted or substituted with one or more of linear or branched _C1-6 alkyl, _NH2 , _NMe2 or 5-6 membered heterocycloalkyl).

In specific compounds of formula IIIa-2a, IIIa-2b, IIIa-2c, IIIa-3a, IIIa-4a or IIIa-5a, R ¹ , R ² , R ³ and R ⁴ are each independently selected from hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —CHO, —C _1-6 alkylC(O)OH, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R ¹ , R ² , R ³ , R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl; and X ³ is absent, hydrogen or 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, —O—(4-8 membered heterocycloalkyl), —C _1-4 alkoxy-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, —O—(5-10 membered heteroaryl), —OC(O)—C _1-4 alkyl-4-8 membered heterocycloalkyl, and X ³ is unsubstituted or substituted with one or more of a linear or branched C _1-6 alkyl, NH ₂ , NMe ₂ or 5-6 membered heterocycloalkyl.

In still further specific embodiments of formula IIIa-2a, IIIa-2b, IIIa-2c, R ¹ , R ² , R ³ and R ⁴ are each independently selected from hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —CHO, —C _1-6 alkylC(O)OH, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R ¹ , R ² , R ³ , R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl, and X ³ is hydrogen or a 4-8 membered heterocycloalkyl, C _{and X 3 is unsubstituted or substituted with one or more of linear or branched C 1-6 alkyl, NH 2 , NMe 2, or 5-6 membered heterocycloalkyl, while in compounds of formula IIIa- 3a} ^, IIIa- _4a , or IIIa, two of R 1 , R ₂ , R ₃ , and R 4 are each independently selected from hydrogen, linear or branched _{C 1-6 alkyl} , and halogen, preferably ^Cl , while ^{R 3 and} R ⁴ are hydrogen; while ^{R 1 ,} R ² , R The other two of ^R3 and ^R4 are hydrogen.

In some embodiments of compounds of Formula IIIa-2a, IIIa-2b, IIIa-2c, IIIa-3a, IIIa-4a, or IIIa-5a, three of R ¹ , R ² , R ³ , and R ⁴ are each independently hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ —O—(CH ₂ ) ₂ —OMe, OCF ₃ , —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-4 alkylamino, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —CHO, —C _1-6 alkylC(O)OH, —C and/or two of R ₁ , R 2 , R ₃ , R ₄ together form a _5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl, while one of R ¹ , R ² , R ³ , R ⁴ is hydrogen; X ³ is hydrogen or a ^4-8 membered heterocycloalkyl, C ^1-4 alkyl ^4-8 membered heterocycloalkyl, —O- ₍ 4-8 membered heterocycloalkyl), —C ^1-4 alkoxy-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, —O-(5-10 membered heteroaryl), —OC(O)—C _1-4 alkyl- _4-8 membered heterocycloalkyl; and X ³ is unsubstituted or substituted with one or more of straight or branched chain C _1-6 alkyl, NH ₂ , NMe ₂ or 5-6 membered heterocycloalkyl.

In some embodiments of compounds of Formula IIIa-2a, IIIa-2b, IIIa-2c, IIIa-3a, IIIa-4a, or IIIa-5a, three of R ¹ , R ² , R ³ , and R ⁴ are independently selected from hydrogen, linear or branched C _1-6 alkyl, linear or branched C _1-6 heteroalkyl, C ₆ aryl, preferably phenyl, CF ₃ , CHF ₂ , —O—CHF ₂ , OCF ₃ , —CN, —CHO, —C _1-6 alkylC(O)OH, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and/or two of R ¹ , R ² , R ³ , R ⁴ together form a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl, while R ¹ , R ² , one of R ³ and R ⁴ is hydrogen, and X ³ is absent, hydrogen or 4-8 membered heterocycloalkyl, C _1-4 alkyl 4-8 membered heterocycloalkyl, —O-(4-8 membered heterocycloalkyl), —C _1-4 alkoxy-(4-8 membered heterocycloalkyl), 5-10 membered heteroaryl, —O-(5-10 membered heteroaryl), —OC(O)—C _1-4 alkyl-4-8 membered heterocycloalkyl, and X ³ is unsubstituted or substituted with one or more of linear or branched C _1-6 alkyl, NH ₂ , NMe ₂ or 5-6 membered heterocycloalkyl.

In some embodiments, the compound of Formula IIIb has the formula IIIb-1
(In the formula,
p is 0, 1 or 2;
Z is a straight or branched chain C _1-6 alkyl, or C _3-6 cycloalkyl, C _1-4 alkoxy or C _1-4 alkyl-C _1-4 alkoxy, and Z is unsubstituted or substituted by C _1-4 alkyl.

In some embodiments of compounds of Formula IIIb, C _1-6 alkyl is chosen from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, iso-hexyl, and neohexyl.

In some embodiments of the compound of Formula IIIb, the C _3-6 cycloalkyl is chosen from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In some embodiments of compounds of Formula IIIb, the C _1-4 alkoxy is selected from methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, and t-butoxy.

In some embodiments of compounds of Formula IIIb, " _{Ci_4} alkyl- _{Ci_4} alkoxy" is selected from methyl-methoxy, methyl-ethoxy, methyl-n-propoxy, methyl-iso-propoxy, methyl-n-butoxy, methyl-iso-butoxy, methyl-t-butoxy, ethyl-methoxy, ethyl-ethoxy, ethyl-n-propoxy, ethyl-iso-propoxy, ethyl-n-butoxy, ethyl-iso-butoxy, ethyl-t-butoxy, propyl-methoxy, propyl-ethoxy, propyl-n-propoxy, propyl-iso-propoxy, propyl-n-butoxy, propyl-iso-butoxy, and propyl-t-butoxy.

In more specific embodiments of compounds of Formula IIIb-1, Z is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, Z is unsubstituted or substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl, and p is 0.

In more specific embodiments of compounds of Formula IIIb, Z is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or t-butoxy, and Z is unsubstituted or substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl; and p is 1.

In still further specific embodiments of compounds of Formula IIIb, Z is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, Z is unsubstituted or substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and p is 2.

In some embodiments, the compound of Formula IIIc is of Formula IIIc-1
(In the formula,
one or two of w ⁴ , w ⁵ , w ⁶ , w ⁷ are selected from C, O, N, NMe, NH or S, while two or three of w ⁴ , w ⁵ , w ⁶ and w ⁷ are C;
R ⁵ , R ⁶ are each independently selected from hydrogen, straight or branched C _1-4 alkyl, CF ₃ , CHF ₂ , halogen, preferably F, Cl, Br, more preferably F or Cl).

In more particular embodiments of compounds of formula IIIc-1, or a pharmaceutically acceptable salt or stereoisomer thereof, R ⁵ , R ⁶ are each independently selected from hydrogen, methyl, ethyl, and CF ₃ .

In some embodiments of the compound of Formula IIIc-1, or a pharmaceutically acceptable salt or stereoisomer thereof, w ⁵ is N, w ⁷ is NMe, and w ⁶ and w ⁴ are C; or w ⁵ is C, w ⁷ is S, and w ⁶ and w ⁴ are C; or w ⁵ is C, w ⁷ is NMe, w ⁶ is N, and w ⁴ is C; or w ⁵ is C, w ⁷ is C, w ⁶ is C, and w ⁴ is S; or w ⁵ is C, w ⁷ is C, w ⁶ is N, and w ⁴ is N; or w ⁵ is O, w 7 is C, w ⁶ is C, and w ⁴ is S; or w ⁵ is NH, w ⁷ is C, w ⁶ is C, and w ⁴ is C ^; or w ⁵ is C, w ⁷ is S, and w or w ⁵ is NH, w ⁷ is C, w ⁶ is C, and w 4 is N; or w ⁵ is C, w ⁷ is N, w ⁶ is C, and w ⁴ is S; or w ⁵ is NH, w ⁷ is N, w ⁶ is C, and w ⁴ is C; or w ⁵ is ^C , w ⁷ is NMe, w ⁶ is C, and w ⁴ is C; or w ⁵ is N, w ⁷ is C, w ⁶ is C, ^{and w 4 is} S; or w ⁵ is C, w ⁷ is C, w ⁶ is S, ^{and w 4 is} N.

In some embodiments of the compound of Formula IIIc-1, or a pharmaceutically acceptable salt or stereoisomer thereof, R ⁵ , R ⁶ are each independently selected from hydrogen, methyl, ethyl, and CF ₃ , and w ⁵ is N, w ⁷ is NMe, and w ⁶ and w ⁴ are C; or w ⁵ is C, w ⁷ is S, and w ⁶ and w ⁴ are C; or w ⁵ is C, w ⁷ is NMe, w ⁶ is N, and w ⁴ is C; or w ⁵ is C, w ⁷ is C, w ⁶ is C, and w ⁴ is S; or w ⁵ is C, w ⁷ is C, w ⁶ is N, and w ⁴ is N; or w ⁵ is O, w ⁷ is C, w ⁶ is C, and w ⁴ is S; or w ⁵ is NH, w ⁷ is C, and w or w ⁵ is C, w ⁷ is S, w ⁶ is C, and w 4 is N; or w ⁵ is NH, w ⁷ is C, w ⁶ is C, and w ⁴ is N; or w ⁵ is C, w ⁷ is N, w ⁶ is C, and w ⁴ is S; or ^{w 5 is} NH, w ⁷ is N, w ⁶ is C, and w ⁴ is C; or w ⁵ is C, w ⁷ is NMe, w ⁶ is ^{C, and w 4 is} C; or w ⁵ is N, w ⁷ is C, w ⁶ is C, and w ⁴ is S ^; or w ⁵ is C, w ⁷ is C, w ⁶ is S, and w ⁴ is N.

In more particular embodiments, the present disclosure, particularly the compounds of formula IIIa and IIIb, is directed to compounds of formula IIIa' or IIIb', or pharmaceutically acceptable salts or stereoisomers thereof:
(In the formula,
n is 1 or 2;
p is 0, 1 or 2;
R ¹ , R ² , R ³ and R ⁴ each represent hydrogen, CF ₃ , linear or branched C _1-4 alkyl, C _{1-4 alkoxy, 4- to 7-} membered heterocycloalkyl, C _1-4 alkyl 4- to 7-membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —OC(O)—C _1-6 alkyl, —N(H)C(O)—C _1-6 alkyl, —C(O)O—C _{1-6 alkyl, —COOH, —C 1-6 alkylC} (O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl or Br, more preferably F or Cl and C ₆ aryl, preferably phenyl, straight or branched C _1-6 alkyl, C _3-6 cycloalkyl or C _1-4 alkoxy;
Z is unsubstituted or substituted with _C1-4 alkyl or _C6 aryl).

In some particular embodiments of compounds of Formula IIIa' or IIIb', n is 1.

In more specific embodiments of compounds of Formula IIIa' or IIIb', p is 0, 1, or 2.

In other embodiments of compounds of Formula IIIa' or IIIb', p is 0 or 1.

In still other embodiments of compounds of Formula IIIa' or IIIb', n is 1 and p is 0, 1, or 2.

In certain other embodiments of compounds of Formula IIIa' or IIIb', n is 1 and p is 0 or 1.

In some embodiments of the compound of Formula IIIa′, or a pharmaceutically acceptable salt or stereoisomer thereof, R ¹ , R ² , and R ³ are defined as above, and R ⁴ is hydrogen, wherein the aromatic ring contains four substituents that are not hydrogen.

In some embodiments of the compound of Formula IIIa′, or a pharmaceutically acceptable salt or stereoisomer thereof, R ¹ and R ² are defined as above, and R ³ and R ⁴ are each hydrogen, wherein the aromatic ring contains three substituents that are not hydrogen.

In some particular embodiments of compounds of formula IIIa′, R ¹ and R ² are hydrogen, 4-7 membered heterocycloalkyl, C _1-4 alkyl 4-7 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _{1-6 alkylamino, —CN, —OC(O)—C 1-6} alkyl, —N(H)C(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH _{2 ,} C Independently selected _{from 1 to 4} alkylhydroxy, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br and phenyl.

In some particular embodiments of compounds of formula IIIa′, R ¹ and R ² are hydrogen, morpholinyl, —(CH ₂ )-morpholinyl, piperazinyl, —(CH ₂ )-piperazinyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C Independently selected _{from 1 to 4} alkylhydroxy, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br and phenyl.

In some particular embodiments of compounds of Formula IIIa′, R ¹ and R ² are independently selected from hydrogen, CF ₃ , OCF ₃ , C _1-4 alkylamino, —CN, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br, and phenyl.

In more particular embodiments of compounds of formula IIIa′, R ¹ and R ² are hydrogen, 4-7 membered heterocycloalkyl, C _1-4 alkyl 4-7 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —OC(O)—C _1-6 alkyl, —N(H)C(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _{1-6 alkylC(O)OH, —C 1-6} alkylC(O)O—C _1-6 alkyl, NH _{2 ,} C _{1 to 4} alkyl are independently selected from hydroxy, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br and phenyl, where n is 1.

In more particular embodiments of compounds of formula IIIa′, R ¹ and R ² are hydrogen, morpholinyl, —(CH ₂ )-morpholinyl, piperazinyl, —(CH ₂ )-piperazinyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _{1 to 4} alkyl are independently selected from hydroxy, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br and phenyl, where n is 1.

In more particular embodiments of compounds of formula IIIa′, R ¹ and R ² are independently selected from hydrogen, CF ₃ , OCF ₃ , C _1-4 alkylamino, —CN, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br, and phenyl; and n is 1.

In some other particular embodiments of compounds of formula IIIa′, R ¹ and R ² are hydrogen, 4-7 membered heterocycloalkyl, C _1-4 alkyl 4-7 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C 1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, _{—C 1-6 alkylC} (O)O—C _1-6 alkyl, NH ₂ , C and p is 0, _{1, or 2} .

In some other particular embodiments of compounds of formula IIIa′, R ¹ and R ² are hydrogen, morpholinyl, —(CH ₂ )-morpholinyl, piperazinyl, —(CH ₂ )-piperazinyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C and p is 0, _{1, or 2} .

In some other particular embodiments of compounds of formula IIIa′, R ¹ and R ² are independently selected from hydrogen, CF ₃ , OCF ₃ , C _1-4 alkylamino, —CN, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br, and phenyl; and p is 0, 1, or 2.

In some other particular embodiments of compounds of formula IIIa′, R ¹ and R ² are hydrogen, 4-7 membered heterocycloalkyl, C _1-4 alkyl 4-7 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —OC(O)—C _1-6 alkyl, —N(H)C(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C and p is _{0 or 1} .

In some other particular embodiments of compounds of formula IIIa′, R ¹ and R ² are hydrogen, morpholinyl, —(CH ₂ )-morpholinyl, piperazinyl, —(CH ₂ )-piperazinyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C and p is _{0 or 1} .

In some other particular embodiments of compounds of formula IIIa′, R ¹ and R ² are independently selected from hydrogen, CF ₃ , OCF ₃ , C _1-4 alkylamino, —CN, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br, and phenyl; and p is 0 or 1.

In still further specific embodiments of compounds of formula IIIa′, R ¹ and R ² are hydrogen, 4-7 membered heterocycloalkyl, C _1-4 alkyl 4-7 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _{1-6 alkylC(O)OH, —C 1-6} alkylC(O)O—C _1-6 alkyl, _{NH 2} , C _{and 1 to 4} alkylhydroxy, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br, and phenyl;

In still further specific embodiments of compounds of formula IIIa′, R ¹ and R ² are hydrogen, morpholinyl, —(CH ₂ )-morpholinyl, piperazinyl, —(CH ₂ )-piperazinyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _{and 1 to 4} alkylhydroxy, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br, and phenyl;

In still further specific embodiments of compounds of formula IIIa′, R ¹ and R ² are independently selected from hydrogen, CF ₃ , OCF ₃ , C _1-4 alkylamino, —CN, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br, and phenyl; n is 1; and p is 0, 1, or 2.

In still further specific embodiments of compounds of formula IIIa′, R ¹ and R ² are hydrogen, 4-7 membered heterocycloalkyl, C _1-4 alkyl 4-7 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —OC(O)—C _1-6 alkyl, —N(H)C(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _{1-6 alkylC(O)OH, —C 1-6} alkylC(O)O—C _1-6 alkyl, _{NH 2} , C Independently selected _{from 1 to 4} alkylhydroxy, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br and phenyl, wherein n is 1 and p is 0 or 1.

In still further specific embodiments of compounds of formula IIIa′, R ¹ and R ² are hydrogen, morpholinyl, —(CH ₂ )-morpholinyl, piperazinyl, —(CH ₂ )-piperazinyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ -OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C Independently selected _{from 1 to 4} alkylhydroxy, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br and phenyl, wherein n is 1 and p is 0 or 1.

In still further specific embodiments of compounds of formula IIIa′, R ¹ and R ² are independently selected from hydrogen, CF ₃ , OCF ₃ , C _1-4 alkylamino, —CN, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br, and phenyl; n is 1; and p is 0 or 1.

In certain embodiments of compounds of Formula IIIb', Z is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, iso-hexyl, neohexyl or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, and Z is unsubstituted or substituted with methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, or _C6 aryl.

In more particular embodiments of compounds of formula IIIb', Z is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, iso-hexyl, neohexyl or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, Z is unsubstituted or substituted with methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl or _C6 aryl; and n is 1.

In more particular embodiments of compounds of formula IIIb', Z is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, iso-hexyl, neohexyl or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, Z is unsubstituted or substituted with methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl or _C6 aryl; and p is 0, 1 or 2.

In more particular embodiments of compounds of formula IIIb', Z is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, iso-hexyl, neohexyl or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, Z is unsubstituted or substituted with methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl or _C6 aryl; and p is 0 or 1.

In still further particular embodiments of compounds of formula IIIb', Z is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, iso-hexyl, neohexyl or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, Z is unsubstituted or substituted with methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl or _C6 aryl; n is 1; and p is 0, 1, or 2.

In still further particular embodiments of compounds of formula IIIb', Z is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, iso-hexyl, neohexyl or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, Z is unsubstituted or substituted with methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl or _C6 aryl, n is 1 and p is 0 or 1.

In a more particular embodiment, the present disclosure is directed to a compound of formula IIIa'-1, or a pharmaceutically acceptable salt or stereoisomer thereof:
(In the formula,
R ¹ , R ² , R ³ , R ⁴ are each independently selected from hydrogen, 4-7 membered heterocycloalkyl, C _1-4 alkyl 4-7 membered heterocycloalkyl, CF ₃ , linear or branched C _1-4 alkyl, C _1-4 alkoxy, CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —OC(O)—C _1-6 alkyl, —N(H)C(O)—C _1-6 alkyl, —C(O)O—C _{1-6 alkyl, —COOH, —C 1-6 alkylC} (O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and C ₆ aryl, preferably phenyl.

In some particular embodiments of compounds of formula IIIa'-1, R ¹ , R ² , R ³ and R ⁴ are hydrogen, 4-7 membered heterocycloalkyl, C _1-4 alkyl 4-7 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _{1-6 alkylamino, —CN, —N(H)C(O)—C 1-6 alkyl} , —OC(O) _{—C 1-6 alkyl, —C(O)O—C 1-6 alkyl} , —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C are independently selected from _1-4 alkylhydroxy, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br or phenyl, preferably from hydrogen, CF ₃ , OCF ₃ , C _1-4 alkylamino, —CN, methyl, ethyl, t-butyl, methoxy, F, Cl and phenyl, more preferably from hydrogen, CF ₃ , methyl, ethyl, t-butyl, methoxy, F, Cl and phenyl.

In some embodiments of the compounds of Formula IIIa'-1, or pharmaceutically acceptable salts or stereoisomers thereof, R ¹ , R ² , and R ³ are defined as above, and R ⁴ is hydrogen, wherein the aromatic ring contains four substituents that are not hydrogen.

In some embodiments of the compounds of Formula IIIa'-1, or pharmaceutically acceptable salts or stereoisomers thereof, R ¹ and R ² are defined as above, and R ³ and R ⁴ are each hydrogen, wherein the aromatic ring contains three substituents that are not hydrogen.

In some embodiments, the compound of formula IIIa'-1 is defined by formula IIIa'-1a, IIIa'-1b, IIIa'-1c, or IIIa'-1d
wherein R ¹ and R ² are each independently selected from hydrogen, 4-7 membered heterocycloalkyl, C _1-4 alkyl 4-7 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —OC(O)—C _1-6 alkyl, —N(H)C(O)—C _1-6 alkyl, —C(O)O—C _{1-6 alkyl, —COOH, —C 1-6 alkylC} (O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-4 alkylhydroxy, linear or branched C _{1-4 alkyl, C 1-4 alkoxy} , halogen, preferably F, Cl, Br, more preferably F or Cl, and C ₆ aryl, preferably phenyl.

In some particular embodiments of compounds of formula IIIa'-1a, IIIa'-1b, IIIa'-1c, or IIIa'-1d, R ¹ and R ² are hydrogen, 4-7 membered heterocycloalkyl, C _1-4 alkyl 4-7 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C 1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, _{—C 1-6 alkylC} (O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C Independently selected _{from 1 to 4} alkylhydroxy, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br and phenyl, preferably hydrogen, CF ₃ , methyl, ethyl, t-butyl, methoxy, F, Cl or phenyl.

In some embodiments of compounds of formula IIIa'-1a, IIIa'-1b, IIIa'-1c, or IIIa'-1d, R ¹ and R ² are independently selected from hydrogen, CF ₃ , OCF ₃ , C _1-4 alkylamino, —CN, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br, and phenyl, preferably hydrogen, CF ₃ , methyl, ethyl, t-butyl, methoxy, F, Cl, or phenyl.

In some embodiments, the compound of formula IIIa'-1 is defined by formula IIIa'-1e, IIIa'-1f, IIIa'-1g, IIIa'-1h, IIIa'-1i, or IIIa'-1j, particularly by formula IIIa'-1h or IIIa'-1g
wherein R ¹ , R ² and R ³ are each independently selected from hydrogen, 4-7 membered heterocycloalkyl, C _1-4 alkyl 4-7 membered heterocycloalkyl, CF ₃ , linear or branched C _{1-4 alkyl, C 1-4 alkoxy} , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C 1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , _{C 1-4 alkylhydroxy} , halogen, preferably F, Cl, Br, more preferably F or Cl, or C ₆ aryl, preferably phenyl.

In some particular embodiments of compounds of formula IIIa'-1e, IIIa'-1f, IIIa'-1g, IIIa'-1h, IIIa'-1i, or IIIa'-1j, R ¹ , R ² , and R ³ are hydrogen, 4-7 membered heterocycloalkyl, C _1-4 alkyl 4-7 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _1-6 alkyl, —COOH, —C _1-6 alkylC(O)OH, —C _{1-6 alkylC(O)O—C 1-6 alkyl} , NH ₂ , C independently selected _{from 1 to 4} alkylhydroxy, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br and phenyl, preferably hydrogen, CF ₃ , methyl, ethyl, t-butyl, methoxy, F, Cl and phenyl;

In some embodiments of compounds of formula IIIa'-1e, IIIa'-1f, IIIa'-1g, IIIa'-1h, IIIa'-1i, or IIIa'-1j, R ¹ , R ² , and R ³ are independently selected from hydrogen, CF ₃ , OCF ₃ , C _1-4 alkylamino, —CN, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br, and phenyl, preferably hydrogen, CF ₃ , methyl, ethyl, t-butyl, methoxy, F, Cl, and phenyl.

In some embodiments, the compound of formula IIIa'-1 is defined by formula IIIa'-1l, IIIa'-1m, or IIIa'-1n:
wherein R ¹ , R ² , R ³ and R ⁴ are each independently selected from hydrogen, 4-7 membered heterocycloalkyl, C _1-4 alkyl 4-7 membered heterocycloalkyl, CF ₃ , linear or branched C _1-4 alkyl, C _1-4 alkoxy, CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _1-6 alkyl, —OC(O)—C _1-6 alkyl, —C(O)O—C _{1-6 alkyl, —COOH, —C 1-6 alkylC} (O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C _1-4 alkylhydroxy, halogen, preferably F, Cl, Br, more preferably F or Cl, and C ₆ aryl, preferably phenyl.

In some particular embodiments of compounds of formula IIIa'-1l, IIIa'-1m, or IIIa'-1n, R ¹ , R ² , R ³ , and R ⁴ are hydrogen, 4-7 membered heterocycloalkyl, C _1-4 alkyl 4-7 membered heterocycloalkyl, CF ₃ , CHF ₂ , —O—(CH ₂ ) ₂ —OMe, OCF ₃ , C _1-6 alkylamino, —CN, —N(H)C(O)—C _{1-6 alkyl, —OC(O)—C 1-6 alkyl} , —C(O)O—C _{1-6 alkyl, —COOH, —C 1-6 alkylC} (O)OH, —C _1-6 alkylC(O)O—C _1-6 alkyl, NH ₂ , C Independently selected _{from 1 to 4} alkylhydroxy, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br and phenyl, preferably hydrogen, CF ₃ , methyl, ethyl, t-butyl, methoxy, F, Cl and phenyl.

In some embodiments of compounds of formula IIIa'-1l, IIIa'-1m, or IIIa'-1n, R ¹ , R ² , R ³ , and R ⁴ are independently selected from hydrogen, CF ₃ , OCF ₃ , C _1-4 alkylamino, —CN, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, F, Cl, Br, and phenyl, preferably hydrogen, CF ₃ , methyl, ethyl, t-butyl, methoxy, F, Cl, and phenyl.

In a more particular embodiment, the present disclosure is directed to a compound of formula IV, or a pharmaceutically acceptable salt or stereoisomer thereof:
(In the formula,
W is
(selected from).

In certain embodiments of compounds of Formula IV, W is
is.

In a more particular embodiment, the present disclosure is directed to a compound of formula IV', or a pharmaceutically acceptable salt or stereoisomer thereof:
(In the formula,
W' is
(selected from).

In certain embodiments of compounds of formula IV', W' is
is.

In a more particular embodiment, the present disclosure is directed to a compound of formula V, or a pharmaceutically acceptable salt or stereoisomer thereof:
(Wherein ^W1 is
(selected from).
In certain embodiments of compounds of Formula V, W ¹ is
is selected from.

In a more particular embodiment, the present disclosure is directed to a compound of formula VI, or a pharmaceutically acceptable salt or stereoisomer thereof:
(In the formula,
^W2 is
(selected from).

In more particular embodiments of the compound of formula VI, ^W2 is:
is selected from.

In a more particular embodiment, the present disclosure is directed to a compound of formula VII, or a pharmaceutically acceptable salt or stereoisomer thereof:
(In the formula,
^W3 is
(selected from).

In more particular embodiments of the compound of formula VII, ^W3 is:
is selected from.

In more specific embodiments, the present disclosure is directed to the specific examples disclosed in Table 1.

In some embodiments, the present disclosure is directed to the (S) enantiomer of a compound of any of Formulas I-VII.

In some embodiments, the present disclosure is directed to the (R) enantiomer of a compound of any of Formulas I-VII.

In some embodiments, the present disclosure is directed to a racemate of any of the compounds of Formulas I-VII.

In a further aspect, the present disclosure is directed to a method of producing a compound of any of Formulas I-VII by General Procedure A.

The compounds of the present disclosure may contain one or more asymmetric centers in the molecule. Compounds without a stereochemistry designation should be understood to include all optical isomers (e.g., diastereomers, enantiomers, etc.) in pure or substantially pure form, and mixtures thereof (e.g., racemic mixtures or enantiomerically enriched mixtures). Methods for preparing such optically active forms (e.g., resolution of racemates by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, chromatographic separation using chiral stationary phases, and other methods) are well known in the art.

The compounds may be isotopically labeled compounds, e.g., compounds containing various isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, or chlorine. The disclosed compounds may exist in tautomeric forms and mixtures, and separate individual tautomers are contemplated. Additionally, some compounds may exhibit polymorphism.

The compounds of the present disclosure include the free form as well as pharmaceutically acceptable salts and stereoisomers thereof. Pharmaceutically acceptable salts include all typical pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of the present disclosure can be synthesized from compounds of the present disclosure containing a basic or acidic moiety by conventional chemical methods; see, for example, Berge et al., "Pharmaceutical Salts," J. Pharm. ScL, 1977:66:1-19. Furthermore, the compounds of the present disclosure also include lyophilized forms and polymorphs of the free form.

For example, conventional pharmaceutically acceptable salts of basic compounds include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and trifluoroacetic acid. Conventional pharmaceutically acceptable salts of acidic compounds include those derived from inorganic bases, including aluminum, ammonium, calcium, copper, ferric acid, ferrous acid, lithium, magnesium, manganic acid, manganous acid, potassium, sodium, and zinc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

The compounds of the present disclosure may exist in solid, i.e., crystalline or amorphous forms (optionally as solvates) or liquid forms. In the solid state, the compounds of the present disclosure may exist in or as mixtures thereof. In crystalline solvates, solvent molecules are incorporated into the crystal lattice during crystallization. Solvate formation can involve non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or aqueous solvents such as water (also called "hydrates"). Crystalline forms (and solvates thereof) may exhibit polymorphism, i.e., they may exist in different crystalline structures, known as "polymorphs," that have the same chemical composition but differ in packing, geometry, and other classificatory characteristics of the crystalline solid state. Polymorphs may therefore have different physical properties, such as shape, density, hardness, deformability, stability, and dissolution characteristics, and may exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which can be used for identification. For example, changing or adjusting the reaction conditions or reagents during the preparation of the compounds of the present disclosure may result in the production of such different polymorphs.

In a further aspect, the present disclosure also provides methods for preparing the disclosed compounds. Typically, they are prepared according to the syntheses shown in the Experimental Section.

In yet another aspect, the present disclosure further provides pharmaceutical compositions comprising a therapeutically effective amount of one or more of the disclosed compounds, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers and/or excipients (also referred to as diluents). An excipient is acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient). The term "therapeutically effective amount," as used herein, refers to an amount of a disclosed compound (neat or in the form of a pharmaceutical composition) effective to produce some desired therapeutic effect.

Pharmaceutical compositions can be in unit dosage forms containing a predetermined amount of a compound of the present disclosure per unit dose. Such units contain a therapeutically effective dose of a compound of the present disclosure or a salt thereof, or a fraction of a therapeutically effective dose, such that multiple unit dosage forms can be administered at a given time to achieve the desired therapeutically effective dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of a compound of the present disclosure or a salt thereof.

The compounds of the present disclosure can be administered by any acceptable means in solid or liquid form, including: (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., intended for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or sustained release formulations; (3) topical application, e.g., as a cream, ointment, or controlled release patch applied to the skin, or as a spray; (4) vaginally or rectally, e.g., as a pessary, cream, or foam; (5) sublingually; (6) ophthalmically; (7) transdermally; (8) nasally; (9) pulmonary; or (10) intrathecally.

As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium, calcium, or zinc stearate, or steric acid), or solvent encapsulating substance, that is involved in carrying or transporting a compound of interest from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of substances that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; and (10) propylene glycol. (11) glycols such as glycol, (12) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, (13) esters such as ethyl oleate and ethyl laurate, (14) buffers such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) pH buffer solutions, (21) polyesters, polycarbonates, and/or polyanhydrides, and (22) other non-toxic, compatible substances used in pharmaceutical formulations.

Such compositions may contain additional components conventional in pharmaceutical preparations, such as wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives and antioxidants, pH modifiers, bulking agents, and additional active agents. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bicarbonate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and (3) metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

Such compositions can be prepared by any method known in the art, for example, by combining the active ingredient with one or more carriers and/or excipients. Examples of various compositions and carriers and/or excipients are well known to those skilled in the art and are described, for example, in Remington: The Science and Practice of Pharmacy. Pharmaceutical Press, 2013; Rowe, Sheskey, Quinn: Handbook of Pharmaceutical Excipients. Pharmaceutical Press, 2009. Excipients that can be used to prepare pharmaceutical compositions can include one or more of buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents, and other known additives to provide a composition suitable for optimal administration.

As indicated above, the compounds of the present disclosure may be in solid or liquid form and may be administered by a variety of routes in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.

In the solid dosage forms of the present disclosure for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules, lozenges), the compound is incorporated into one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or one or more of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and/or acacia; (3) humectants, such as glycerol; (4) soluble solids, such as agar, calcium carbonate, potato starch, or tapioca starch, alginic acid, certain silicates, and sodium carbonate; The pharmaceutical composition may be mixed with any of the following: (1) disintegrants such as ammonium hydroxide, (2) dissolution retardants such as paraffin, (3) absorption enhancers such as quaternary ammonium compounds, and surfactants such as poloxamers and sodium lauryl sulfate, (4) wetting agents such as cetyl alcohol, glycerol monostearate, and nonionic surfactants, (5) absorbents such as kaolin and bentonite clay, (6) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof, (7) coloring agents, and (8) controlled-release agents such as crospovidone or ethylcellulose. For capsules, tablets, and pills, the pharmaceutical composition may also contain buffering agents. Similar solid compositions may also be used as fillers in soft and hard-shell gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms of the pharmaceutical compositions of the present disclosure, such as dragees, capsules, pills, and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical compounding art. They can also be formulated to achieve delayed or controlled release of the active ingredient therein, using, for example, various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and/or microspheres to achieve the desired release profile. They can also be formulated for rapid release, for example, by lyophilization. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents, and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the gastrointestinal tract, optionally, with a delayed release. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the excipients described above.

Liquid dosage forms for oral administration of the compounds of the present disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain, for example, an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. Oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, coloring agents, flavors, and preservatives.

In suspension form, the compound may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

Dosage forms for rectal or vaginal administration of the compounds of the present disclosure include suppositories, which can be prepared by mixing one or more compounds of the present disclosure with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate; the suppositories are solid at room temperature but liquid at body temperature, and thus melt in the rectum or vaginal cavity to release the active compound(s). Other suitable forms include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.

Dosage forms for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. Such ointments, pastes, creams, and gels may contain, in addition to the compounds of the present disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

Dosage forms such as powders and sprays for administering the compounds of the present disclosure may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Dosage forms, such as transdermal patches, for administering the compounds of the present disclosure can contain absorption enhancers or retardants to increase or decrease the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel. Other contemplated dosage forms include ophthalmic formulations, eye ointments, powders, solutions, and the like. It will be understood that all contemplated compositions must be stable under the conditions of manufacture and storage and preserved against the contaminating action of microorganisms, such as bacteria and fungi.

Dosage levels of the compounds of the present disclosure in the pharmaceutical compositions of the present disclosure may be adjusted to obtain an amount of the compounds of the present disclosure effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without causing harm to the patient. The optimal dosage will depend on a variety of factors, including the nature of the particular compound of the present disclosure used, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound used, the rate and extent of absorption, the duration of treatment, other drugs, compounds, and/or substances used in combination with the particular compound, the age, sex, weight, condition, general health, and medical history of the patient being treated, and similar factors well known in the medical arts. A medical practitioner of ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.

Typically, a suitable daily dose of a compound of the present disclosure will be the amount of compound that is the lowest effective dose to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. In general, oral, intravenous, intracerebroventricular, and subcutaneous doses of a compound of the present disclosure for a patient, when used for the indicated analgesic effect, will range from about 0.0001 to about 100 mg per kilogram of recipient (patient, mammal) body weight per day, more usually 0.1 to 100 mg/kg. Acceptable daily dosages can be from about 1 to about 1000 mg/day, and for example, from about 1 to about 100 mg/day.

An effective dose of a compound of the present disclosure may be administered as two, three, four, five, six, or even more divided doses administered separately at appropriate intervals, if necessary, in unit dosage forms over a designated period of time (daily, weekly, or monthly). The preferred dose will also depend on the factors noted above, e.g., administration, and can be readily arrived at by one of ordinary skill in the pharmaceutical or formulation arts.

The compounds of the present disclosure modulate the activity of cereblon. Accordingly, the compounds and compositions of the present disclosure may be useful as pharmaceuticals, i.e., in therapy, more particularly for the treatment of cancers, as described in more detail below. Accordingly, in a further aspect, the present disclosure provides a method of treating a mammal, e.g., a human, suffering from a cancer, as described in more detail below. The term "treatment" is intended to encompass prevention, therapy, and cure. Such treatment comprises administering to the mammal, e.g., a human, a therapeutically effective amount of a compound of Formula I, or a salt thereof (or a pharmaceutical composition containing a therapeutically effective amount of a compound of Formula I, or a salt thereof).

Accordingly, the present disclosure is directed to the use of a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, for the treatment of a disease associated with or caused by GSPT1, particularly cancer, as described in detail below, in a mammal, e.g., a human.

In certain embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts or stereoisomers thereof, or pharmaceutical compositions thereof, are used to treat GSPT1-associated cancers, such as glioma, thyroid cancer, lung cancer, colorectal cancer, head and neck cancer, gastric cancer, liver cancer, pancreatic cancer, renal cancer, urothelial cancer, prostate cancer, testicular cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, melanoma, and multiple myeloma.

Such uses (or methods of treatment) in a subject include administering to a subject in need of such treatment by targeting cereblon a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

The present disclosure contemplates administration of the compounds of the present disclosure alone or in combination with one or more additional therapeutic agents that are other tyrosine kinase inhibitors, such as: erlotinib hydrochloride (e.g., Tarceva® by Genentech/Roche), linifanib (or ABT869 by Genentech), sunitinib malate (e.g., Sutent® by Pfizer), bosutinib (or SKI-606, as described in U.S. Pat. No. 6,780,996), dasatinib (e.g., Bristol-Myers Squibb), rifaxitinib (e.g., rifaxitinib ... Sprycel® by Squibb), Almara (e.g. pazopanib, e.g. Votrient® by GlaxoSmithKline), imatinib and imatinib mesylate (e.g. Gilvec® and Gleevec® by Novartis); vascular endothelial growth factor (VEG) receptor inhibitors (bevacizumab or Avastin® by Genentech/Roche), axitinib (or AG013736 as described in WO 01/002369), brivanib alaninate (or BMS-582664), motesanib (or EGFR-14164 as described in PCT AMG-706 as described in WO 02/066470), pasireotide (e.g. SOM230 as described in WO 02/010192), sorafenib (e.g. Nexavar®); HER2 receptor inhibitors: trastuzumab (e.g. Herceptin® by Genentech/Roche), neratinib (or HKI-272 as described in WO 05/028443), lapatinib or lapatinib ditosylate (e.g. Tykerb® by GlaxoSmithKline); CD20 antibodies: rituximab anti-cancer drugs: ribavirin (e.g., Riuxan® and MabThera® by Genentech/Roche), tositumomab (e.g., Bexxar® by GlaxoSmithKline), ofatumumab (e.g., Arzerra® by GlaxoSmithKline); Bcr/Abl kinase inhibitors: nilotinib hydrochloride (e.g., Tasigna® by Novartis); DNA synthesis inhibitors: capecitabine (e.g., Xeloda® by Roche), gemcitabine hydrochloride (e.g., Eli antitumor agents: oxaliplatin (e.g., Eloxatin (European Pharma, Sanofi-Aventis, as described in US Pat. No. 4,169,846)); epidermal growth factor receptor (EGFR) inhibitors: gefitinib (e.g., Iressa (European Pharma, Sanofi-Aventis, as described in US Pat. No. 4,169,846)); (m) CD40 inhibitors: dacetuzumab (e.g., by Seattle Genetic Research), panitumumab (e.g., Vectibix® by Amgen); HER dimerization inhibitors: pertuzumab (e.g., by Genentech); human granulocyte colony-stimulating factor (G-CSF) modulators: filgrastim (e.g., by Neupogen® by Amgen); immunomodulators: afutuzumab (e.g., by Roche®), pegfilgrastim (e.g., by Amgen), lenalidomide (e.g., CC-5013, e.g., Revlimid®), thalidomide (e.g., Thalomid®); (m) CD40 inhibitors: dacetuzumab (e.g., by Seattle Genetic Research), SGN-40 or huS2C6 by Genetics, Inc); apoptosis-inducing receptor agonists (PARA): dulanermin (e.g., AMG-951 by Amgen/Genentech); hedgehog antagonists: vismodegib (or GDC-0449 as described in WO 06/028958); PI3K inhibitors: pictilisib (or GDC-0449 as described in WO 09/036082 and WO 09/055730); 0941), dactolisib (or BEZ235 or NVP-BEZ235 as described in WO 06/122806); phospholipase A2 inhibitors: anagrelide (e.g., Agrylin®); BCL-2 inhibitors: navitoclax (or ABT-263 as described in WO 09/155386); mitogen-activated protein kinase kinase (MEK) inhibitors: XL-518 (Cas no. 1029872-29-4, ACC Corp.); aromatase inhibitors: exemestane (e.g., Aromasin® by Pfizer), letrozole (e.g., Femara® by Novartis), anastrozole (e.g., Arimidex®); topoisomerase I inhibitors: irinotecan (e.g., Camptosar® by Pfizer), topotecan hydrochloride (e.g., Hycamtin® by GlaxoSmithKline); topoisomerase II inhibitors: etoposide (e.g., VP-16 and etoposide phosphate, e.g., Toposar®, VePesid®, and Etopophos®), teniposide (e.g., VM-26, e.g., Vumon®), (R); mTOR inhibitors: temsirolimus (e.g., Torisel® by Pfizer), ridaforolimus (formerly known as deferolimus (or AP23573 and MK8669 described in WO 03/064383), everolimus (e.g., Afinitor® by Novartis); osteoclast bone resorption inhibitors: zoledronic acid (or Zometa® by Novartis); CD33 antibody drug conjugates: gemtuzumab ozogamicin (e.g., Mylotarg® by Pfizer/Wyeth); CD22 antibody drug conjugates: inotuzumab ozogamicin (also called CMC-544 and WAY-207294, Hangzhou) CD20 antibody drug conjugates: ibritumomab tiuxetan (e.g., Zevalin®); somatostain analogs: octreotide (e.g., octreotide acetate, e.g., Sandostatin® and Sandostatin®); LAR®); synthetic interleukin-11 (IL-11): oprelvekin (e.g., Neumega® by Pfizer/Wyeth); synthetic erythropoietin: darvepoetin alfa (e.g., Aranesp® by Amgen); receptor activator of nuclear factor kappa B (RANK) inhibitors: denosumab (e.g., Prolia® by Amgen); thrombopoietin mimetic peptibody: romiplostim (e.g., Nplate® by Amgen); cell proliferation stimulator: palifermin (e.g., Keepivance® by Amgen); anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies: figitumumab (e.g., ACC anti-CS1 antibodies: elotuzumab (HuLuc63, CAS number 915296-00-3); CD52 antibodies: alemtuzumab (e.g., Campath®); CTLA-4 inhibitors: tremelimumab (IgG2 monoclonal antibody by Pfizer, formerly known as ticilimumab, CP-675,206), ipilimumab (CTLA-4 antibody, e.g., MDX-010, CAS number 477202-00-9); histone deacetylase inhibitors (HDIs): vorinostat (e.g., Zolinza ( alkylating agents: temozolomide (e.g., Temodar® and Temodal® by Schering-Plough/Merck), dactinomycin (e.g., actinomycin-D and e.g., Cosmegen®), melphalan (e.g., L-PAM, L-sarcolysin, and phenylalanine mustard, e.g., Alkeran®), altretamine (e.g., hexamethylmelamine (HMM), e.g., Hexalen®), carmustine (e.g., BiCNU®), bendamustine (e.g., Treanda®). , busulfan (e.g., Busulfex® and Myleran®), carboplatin (e.g., Paraplatin®), lomustine (e.g., CCNU, e.g., SeeNU®), cisplatin (e.g., CDDP, e.g., Platinol® and Platinol®-AQ), chlorambucil (e.g., Leukeran®), cyclophosphamide (e.g., Cytoxan® and Neosar®), dacarbazine (e.g., DTIC, DIC, and imidazole carboxamides, e.g., DTIC-Dome®), (registered trademark)), altretamine (e.g., hexamethylmelamine (HMM) e.g., Hexalen®), ifosfamide (e.g., Ifex®), procarbazine (e.g., Matulane®), mechlorethamine (e.g., nitrogen mustard, mustine, and mechloroethamine hydrochloride, e.g., Mustargen®), streptozocin (e.g., Zanosar®), thiotepa (e.g., thiophosphoamide, TESPA, and TSPA, e.g., Thioplex®); biological response modifiers: bacillus Calmette-guerin (e.g., TheraCys® and TICE® BCG), denileukin diftitox (e.g., Ontak®); antitumor antibiotics: doxorubicin (e.g., Adriamycin® and Rubex®), bleomycin (e.g., lenoxane®), daunorubicin (e.g., daurubicin hydrochloride, daunomycin®), cin and rubidomycin hydrochloride, e.g., Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposomal, e.g., DaunoXome®), mitoxantrone (e.g., DHAD, e.g., Novantrone®), epirubicin (e.g., Ellence™), idarubicin (e.g., Idamycin®, Idamycin PFS®), mitomycin C (e.g., Mutamycin®); anti-microtubule agents: estramustine (e.g., Emcyl®); cathepsin K inhibitors: odanacatib (or MK-0822 by Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, as described in WO 03/075836); epothilone B analogs: ixabepilone (e.g., Bristol-Myers Squibb); Lxempra® by Squibb); heat shock protein (HSP) inhibitors: tanespimycin (17-allylamino-17-demethoxygeldanamycin, e.g., KOS-953 and 17-AAG by SIGMA, as described in US 4,261,989); TpoR agonists: eltrombopag (e.g., Promacta® and Rev by GlaxoSmithKline);

antimitotics: docetaxel (e.g., Taxotere® by Sanofi-Aventis); adrenal steroid inhibitors: aminoglutethimide (e.g., Cytadren®); antiandrogens: nilutamide (e.g., Nilandron® and Anandron®), bicalutamide (sold under the brand name Casodex®), flutamide (e.g., Fu lexin™); androgens: fluoxymesterone (e.g. halotestin®); proteasome inhibitors: bortezomib (e.g. Velcade®); CDK1 inhibitors: alvocidib (e.g. fluvopiridol or HMR-1275 as described in US 5,621,002); gonadotropin-releasing hormone (GnRH) receptor agonists: leuprolide or leuprolide acetate (e.g. Viadure® by Bayer AG, Eligard® by Sanofi-Aventis and Abbott Lupron® by Lab); taxane antineoplastics: cabazitaxel, larotaxel; 5HT1a receptor agonists: xaliproden (or SR57746 described in US 5,266,573); HPC vaccines: Cervarix® marketed by GlaxoSmithKline, Gardasil® marketed by Merck; iron chelators: deferasirox (e.g. Exjade® by Novartis); antimetabolites: claribine (2-chlorodeoxyadenosine, e.g. leust tatin®), 5-fluorouracil (e.g., Adrucil®), 6-thioguanine (e.g., Purinethol®), pemetrexed (e.g., Alimta®), cytarabine (e.g., arabinosylcytosine (Ara-C), e.g., Cytosar-U®), cytarabine liposomal (e.g., liposomal Ara-C, e.g., DepoCyt™), decitabine (e.g., Dacogen®), hydroxyurea (e.g., Hydrea®, Droxia™, and Mylo cel™), fludarabine (e.g., Fludara®), floxuridine (e.g., FUDR®), cladribine (e.g., 2-chlorodeoxyadenosine (2-CdA), e.g., Leustatin®), methotrexate (e.g., amethopterin, methotrexate sodium (MTX), e.g., Rheumatrex® and Trexall®), pentostatin (e.g., Nipent®); bisphosphonates: pamidronate (e.g., Aredia®), zoledronic acid (e.g., demethylating agents: 5-azacytidine (e.g., Vidaza®), decitabine (e.g., Dacogen®); plant alkaloids: paclitaxel protein-bound (e.g., Abraxane®), vinblastine (e.g., vinblastine sulfate, vincaleukoblastine, and VLB, e.g., Alkaban-AQ® and Velban®), vincristine (e.g., vincristine sulfate, LCR, and VCR, e.g., Oncovin® and Vincasar®), Pfs®), vinorelbine (e.g., Navelbine®), paclitaxel (e.g., Taxol and Onxal™); retinoids: alitretinoin (e.g., Panretin®), tretinoin (all-trans retinoic acid, e.g., ATRA, e.g., Vesanoid®), isotretinoin (13-cis-retinoic acid, e.g., Accutane®, Amnesteem®, Claravis®, Clarus®, Dextromethorphan®, cutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (e.g., Targretin®); glucocorticosteroids: hydrocortisone (e.g., cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and e.g., Ala-Cort®, hydrocortisone phosphate, Solu-Cortef®, Hydrocort Acetate®, and Lanacort®), dexamethasone, prednisolone (e.g., Delta-Cortel®, Orapred®, Pediapred®, and Prelone®), prednisone (e.g., Deltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisolone (e.g., 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, e.g., Duralone®, Medralone®, Medrol®, M-Prednisol® and Solu-Medrol®); cytokines: interleukin-2 (e.g., aldesleukin and IL-2, e.g., Proleukin®), interleukin-11 ( for example, oprevelkin, e.g., Neumega®), alpha interferon alpha (e.g., IFN-alpha, e.g., Intron® A and Roferon-A®); luteinizing hormone-releasing hormone (LHRH) agonists: goserelin (e.g., Zoladex®); progesterone: megestrol (e.g., megestrol acetate, e.g., Megace®); various cytotoxic agents: arsenic trioxide (e.g., Trisenox®), asparaginase (e.g., L-asparaginase, Erwinia®), L-asparaginase, e.g., Elspar® and Kidrolase®); antinausea medications: NK-1 receptor antagonists: casopitant (e.g., Rezonic® and Zunrisa® by GlaxoSmithKline); and cytoprotectants: amifostine (e.g., Ethyol®), leucovorin (e.g., leucovorin calcium, citrovorum factor, and folinic acid).

General Procedure A:

II: To a solution of 5-bromo-2-methylbenzoic acid (100 g, 465 mmol, 1.00 equiv.) in methanol (700 mL) was added sulfuric acid (31.3 g, 313 mmol, 0.672 equiv.) dropwise at 0°C. The mixture was stirred at 25°C for 1 hour and then heated to 70°C for 12 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The residue was poured into ice-water (200 mL) and basified to pH = 8 with solid sodium carbonate. The aqueous phase was extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give methyl 5-bromo-2-methylbenzoate II (113 g, crude) as a yellow solid. This product was carried on to the next step without purification.

III: To a solution of methyl 5-bromo-2-methyl-benzoate II (113 g, 493 mmol, 1.00 equiv.) in N,N-dimethylformamide (300 mL) was added copper(I) cyanide (66.3 g, 1.50 equiv.). The mixture was stirred at 150° C. for 12 hours. The mixture was slowly quenched with ice and then extracted with ethyl acetate (2×500 mL). The aqueous phase was extracted with ethyl acetate (2×300 mL). The combined organic phase was washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=0/1 to 100/1) to give methyl 5-cyano-2-methyl-benzoate III (61.0 g, 348 mmol, 70% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ -d) δ = 8.22 (d, J = 1.5 Hz, 1H), 7.67 (dd, J = 1.7, 7.9 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 3.93 (s, 3H), 2.68 (s, 3H).

IV: To a solution of methyl 5-cyano-2-methyl-benzoate III (61.0 g, 348 mmol, 1.00 equiv.) and N-bromosuccinimide (75.8 g, 383 mmol, 1.10 equiv.) in carbon tetrachloride (650 mL) was added benzoyl peroxide (8.43 g, 34.8 mmol, 0.100 equiv.). The mixture was stirred at 80° C. for 12 hours. The mixture was concentrated in vacuo, suspended in water (500 mL), and then extracted with ethyl acetate (2×500 mL). The aqueous phase was extracted with ethyl acetate (2×300 mL). The combined organic phases were washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 0/1 to 5/1) to give methyl 2-(bromomethyl)-5-cyanobenzoate IV (80.0 g, 315 mmol, 90% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ -d) δ = 8.20 (d, J = 1.6 Hz, 1H), 7.70 (dd, J = 1.8, 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 4.89 (s, 2H), 3.91 (s, 3H).

V: To a solution of methyl 2-(bromomethyl)-5-cyano-benzoate IV (40 g, 157 mmol, 1.00 equiv.) and 3-aminopiperidine-2,6-dione (25.9 g, 157 mmol, 1.00 equiv., hydrochloric acid) in dimethyl sulfoxide (200 mL) was added triethylamine (65.7 mL, 3.00 equiv.). The mixture was stirred at 100° C. for 2 hours. The crude product was triturated with water (300 mL). The mixture was filtered, the filtrate was concentrated in vacuo, and the solid was then triturated with methanol (30.0 mL). The residue was filtered, and the filtrate was concentrated in vacuo to give 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-carbonitrile V (21.0 g, 78.0 mmol, 49% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 11.01 (s, 1H), 8.20 (s, 1H), 8.09 (dd, J = 1.5, 7.9 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 5.15 (dd, J = 5.1, 13.3 Hz, 1H), 4.64 - 4.40 (m, 2H), 2.99 - 2.85 (m, 1H), 2.65 - 2.56 (m, 1H), 2.44 - 2.34 (m, 1H), 2.03 (dtd, J = 2.0, 5.2, 12.5 Hz, 1H).

VI: 2-(2,6-Dioxo-3-piperidyl)-3-oxo-isoindoline-5-carbonitrile. To a solution of V (5.00 g, 18.6 mmol, 1.00 equiv.) and hydrochloric acid (12 M, 5.00 mL, 3.23 equiv.) in methanol (500 mL) under nitrogen was added platinum(IV) oxide (1.05 g, 4.64 mmol, 0.250 equiv.). The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25° C. for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was triturated with ethyl alcohol (10.0 mL), the mixture was filtered, and the filtrate was dried in vacuo to give 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride VI (5.30 g, 17.1 mmol, 92% yield, hydrochloric acid) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 10.99 (s, 1H), 8.54 (br s, 3H), 7.89 (d, J = 0.7 Hz, 1H), 7.75 (dd, J = 1.6, 7.8 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.54 - 4.30 (m, 2H), 4.14 (q, J = 5.3 Hz, 2H), 2.97 - 2.85 (m, 1H), 2.65 - 2.57 (m, 1H), 2.44 - 2.38 (m, 1H), 2.01 (dtd, J = 2.0, 5.2, 12.5 Hz, 1H).
VII:

Variant i): To a solution of 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride VI (1.00 eq., hydrochloride salt) and triethylamine (3.0 eq.) in N,N-dimethylformamide (0.15 M) was added isocyanate R-NCO (1 eq.) (0.5 M) in N,N-dimethylformamide at 0°C. The mixture was stirred at room temperature for 45 minutes. Polymer-supported trisamine (2.0 eq.) was added and stirred for 30 minutes. The mixture was filtered, washed with N,N-dimethylformamide, and the filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (Biotage SNAP ultra, 0-15% methanol in dichloromethane) to give the final urea-compound VII as a solid.

Variation ii): To a solution of 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride VI (1.00 equivalents, hydrochloride salt) and triethylamine (1.10 equivalents) in N,N-dimethylformamide (0.1 M) was added isocyanate R-NCO (1.10 equivalents) at 0°C. The mixture was stirred at 25°C for 1 hour. The mixture was quenched by adding methanol and concentrated in vacuo. The residue was purified by preparative HPLC (column: Shim-pack C18 150*25*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 10%-40%, 10 minutes) and lyophilized to give the final urea-compound VII as a solid.

Variant iii): To a solution of 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride VI (0.8-1.3 equivalents, hydrochloride salt) and triethylamine (1.2-20 equivalents) in a polar aprotic solvent (dimethylformamide, dichloromethane, or tetrahydrofuran, 0.03-0.71 M) was added O-phenylcarbamate R-N(CO)O-Ph (0.8-2 equivalents). The reaction was stirred at a temperature ranging from 20-60°C for 1-24 hours. The reaction was either extracted (the mixture was diluted with water and extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure), or the reaction was directly concentrated under reduced pressure (with or without predilution with DMSO and/or filtration) to give a residue. Unless otherwise specified, the resulting residue was purified by reverse-phase preparative HPLC or by trituration (ethyl acetate was added and the mixture was cooled to 15°C for 5 minutes; the precipitate was filtered and dried). The purified compound was lyophilized to give the final urea compound VII as a solid.

Variant iv): To a solution of 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride VI (1.00 equiv., hydrochloride salt) and triethylamine (1.10-3.00 equiv.) in a polar aprotic solvent (dimethylformamide or dichloromethane, 0.09-0.33 M) at 0° C. or 20° C. was added the isocyanate R—NCO (1.00-5.00 equiv., neat or dropwise as a solution in dichloromethane). The reaction was stirred for 1-12 hours at a temperature range of 20-30° C. Unless otherwise specified, the reaction was concentrated under reduced pressure (with or without predilution with DMSO and/or filtered) to give a residue. Unless otherwise specified, the resulting residue was purified by reverse-phase preparative HPLC. The purified compound was lyophilized to give the final urea compound VII as a solid.
Table 1: Specific examples

Compound 1: For its preparation, general procedure A with variant i) was used in 75% yield from compound VI using phenyl-isocyanate. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.61 (s, 1H), 7.67 (s, 1H), 7.60 - 7.53 (m, 2H), 7.43 - 7.37 (m, 2H), 7.25 - 7.18 (m, 2H), 6.93 - 6.86 (m, 1H), 6.74 (t, J = 6.1 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 17.1 Hz, 1H), 4.40 (d, J = 6.0 Hz, 2H), 4.31 (d, J = 17.1 Hz, 1H), 2.96 - 2.86 (m, 1H), 2.64 - 2.56 (m, 1H), 2.45 - 2.33 (m, 1H), 2.04 - 1.96 (m, 1H). MS (ESI) m/z 393.1 [M+H] ⁺

Compound 2: Its preparation used general procedure A with variant i) in 65% yield from compound VI using 4-chloro-phenyl-isocyanate. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 8.79 (s, 1H), 7.66 (s, 1H), 7.58 - 7.54 (m, 2H), 7.47 - 7.41 (m, 2H), 7.29 - 7.22 (m, 2H), 6.81 (t, J = 6.0 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 17.1 Hz, 1H), 4.40 (d, J = 6.0 Hz, 2H), 4.30 (d, J = 17.1 Hz, 1H), 2.96 - 2.85 (m, 1H), 2.64 - 2.55 (m, 1H), 2.45 - 2.33 (m, 1H), 2.04 - 1.95 (m, 1H). MS (ESI) m/z 427.1 [M+H, ^Cl35 ] ⁺

Compound 3: General procedure A with variant i) was used for its preparation in 62% yield from compound VI using 3-chloro-phenyl-isocyanate. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.85 (s, 1H), 7.68 - 7.67 (m, 1H), 7.67 - 7.66 (m, 1H), 7.58 - 7.54 (m, 2H), 7.26 - 7.19 (m, 2H), 6.95 - 6.93 (m, 1H), 6.84 (t, J = 6.1 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 17.1 Hz, 1H), 4.40 (d, J = 6.0 Hz, 2H), 4.31 (d, J = MS (ESI) m/z 427.1 [M+H, Cl ³⁵ ] ⁺

Compound 4: General procedure A with variant i) was used for its preparation in 71% yield from compound VI using 2-chloro-phenyl-isocyanate. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 8.19 - 8.13 (m, 2H), 7.69 (d, J = 1.2 Hz, 1H), 7.61 - 7.54 (m, 3H), 7.44 - 7.38 (m, 1H), 7.28 - 7.21 (m, 1H), 7.00 - 6.93 (m, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.48 - 4.42 (m, 3H), 4.32 (d, J = 17.1 Hz, 1H), 2.97 - 2.87 (m, 1H), 2.65 - 2.57 (m, 1H), 2.46 - 2.35 (m, 1H), 2.05 - 1.97 (m, 1H). MS (ESI) m/z 427.1 [M+H, Cl ³⁵ ] ⁺

Compound 5: General procedure A with variant i) was used for its preparation in 73% yield from compound VI using 4-methoxy-phenyl-isocyanate. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.41 (s, 1H), 7.68 - 7.64 (m, 1H), 7.58 - 7.54 (m, 2H), 7.35 - 7.27 (m, 2H), 6.86 - 6.78 (m, 2H), 6.64 (t, J = 6.1 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 17.1 Hz, 1H), 4.38 (d, J = 6.0 Hz, 2H), 4.30 (d, J = 17.1 Hz, 1H), 3.69 (s, 3H), 2.96 - 2.86 (m, 1H), 2.64 - 2.56 (m, 1H), 2.45 - 2.34 (m, 1H), 2.04 - 1.96 (m, 1H). MS (ESI) m/z 423.1 [M+H] ⁺

Compound 6: General procedure A with variant i) was used for its preparation in 79% yield from compound VI using 3-methoxy-phenyl-isocyanate. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.64 (s, 1H), 7.68 - 7.64 (m, 1H), 7.58 - 7.54 (m, 2H), 7.18 - 7.08 (m, 2H), 6.92 - 6.86 (m, 1H), 6.74 (t, J = 6.0 Hz, 1H), 6.51 - 6.45 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 17.1 Hz, 1H), 4.40 (d, J = 6.0 Hz, 2H), 4.31 (d, J = 17.1 Hz, 1H), 3.70 (s, 3H), 2.96 - 2.86 (m, 1H), 2.64 - 2.56 (m, 1H), 2.45 - 2.33 (m, 1H), 2.04 - 1.96 (m, 1H). MS (ESI) m/z 423.1 [M+H] ⁺

Compound 7: General procedure A with variant i) was used for its preparation in 82% yield from compound VI using 2-methoxy-phenyl-isocyanate. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.11 - 8.07 (m, 1H), 8.05 (s, 1H), 7.67 - 7.64 (m, 1H), 7.58 - 7.54 (m, 2H), 7.41 (t, J = 5.9 Hz, 1H), 6.98 - 6.95 (m, 1H), 6.90 - 6.86 (m, 1H), 6.85 - 6.81 (m, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 (d, J = 17.1 Hz, 1H), 4.41 (d, J = 5.9 Hz, 2H), 4.31 (d, J = 17.1 Hz, 1H), 3.84 (s, 3H), 2.95 - 2.85 (m, 1H), 2.64 - 2.56 (m, 1H), 2.44 - 2.35 (m, 1H), 2.03 - 1.97 (m, 1H). MS (ESI) m/z 423.1 [M+H] ⁺

Compound 8: Its preparation used general procedure A according to variant ii) in 44% yield from compound VI using 4-chloro-3-methyl-phenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 8.75 (s, 1H), 7.67 (s, 2H), 7.57 (s, 2H), 7.22 - 7.11 (m, 2H), 6.82 (br t, J = 5.9 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.36 (m, 3H), 4.36 - 4.26 (m, 1H), 2.98 - 2.85 (m, 1H), 2.60 (br dd, J = 2.0, 15.5 Hz, 1H), 2.46 - 2.37 (m, 1H), 2.24 (s, 3H), 2.06 - 1.95 (m, 1H). MS (ESI) m/z 441.2 [M+H] ⁺

Compound 9: Its preparation used general procedure A according to variant ii) in 51% yield from compound VI using 4-bromo-3-methyl-phenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.52 (s, 1H), 7.66 (s, 1H), 7.56 (d, J = 0.9 Hz, 2H), 7.34 - 7.27 (m, 2H), 7.26 - 7.20 (m, 2H), 6.68 (t, J = 6.0 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.34 (m, 3H), 4.34 - 4.26 (m, 1H), 2.96 - 2.84 (m, 1H), 2.59 (td, J = 1.9, 15.4 Hz, 1H), 2.43 - 2.36 (m, 1H), 2.04 - 1.94 (m, 1H), 2.04 - 1.94 (m, 1H), 1.24 (s, 9H). MS (ESI) m/z 449.3 [M+H] ⁺

Compound 10: For its preparation general procedure A according to variant ii) was used in 45% yield from compound VI using tert-butyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 7.59 (s, 1H), 7.56 - 7.52 (m, 1H), 7.51 - 7.47 (m, 1H), 6.20 (t, J = 6.1 Hz, 1H), 5.77 (s, 1H), 5.10 (dd, J = 5.0, 13.2 Hz, 1H), 4.46 - 4.30 (m, 2H), 4.27 (d, J = 6.1 Hz, 2H), 2.96 - 2.86 (m, 1H), 2.62 (br s, 1H), 2.43 - 2.34 (m, 1H), 2.04 - 1.96 (m, 1H), 1.23 (s, 9H). MS (ESI) m/z 373.3 [M+H] ⁺

Compound 11: For its preparation, general procedure A according to variant ii) was used in 46% yield from compound VI using 2-tert-butyl-phenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 7.69 (s, 1H), 7.56 (s, 2H), 7.38 (s, 1H), 7.33 (dd, J = 1.2, 7.8 Hz, 1H), 7.28 - 7.23 (m, 1H), 7.18 - 7.12 (m, 1H), 7.08 (br t, J = 6.7 Hz, 2H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.52 - 4.38 (m, 3H), 4.35 - 4.27 (m, 1H), 2.98 - 2.85 (m, 1H), 2.60 (br MS (ESI) m/z 449.1 [M+H] ⁺

Compound 12: General procedure A according to variant ii) was used for its preparation in 27% yield from compound VI using iso-propyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 7.60 (s, 1H), 7.52 (q, J = 7.7 Hz, 2H), 6.29 (br t, J = 6.0 Hz, 1H), 5.82 (d, J = 7.8 Hz, 1H), 5.11 (dd, J = 5.1, 13.4 Hz, 1H), 4.49 - 4.37 (m, 1H), 4.34 - 4.25 (m, 3H), 3.75 - 3.63 (m, 1H), 2.98 - 2.83 (m, 1H), 2.60 (br d, J = 16.9 Hz, 1H), 2.39 (br dd, J = 4.5, 13.1 Hz, 1H), 2.05 - 1.96 (m, 1H), 1.04 (d, J = 6.5 Hz, 6H). MS (ESI) m/z 359.1 [M+H] ⁺

Compound 13: For its preparation general procedure A according to variant ii) was used in 51% yield from compound VI using n-hexyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 7.60 (s, 1H), 7.54 - 7.48 (m, 2H), 6.38 (br t, J = 5.9 Hz, 1H), 5.95 (br s, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.46 - 4.38 (m, 1H), 4.33 - 4.26 (m, 3H), 3.03 - 2.96 (m, 2H), 2.96 - 2.86 (m, 1H), 2.60 (br d, J = 17.7 Hz, 1H), 2.39 (br dd, J = 4.5, MS (ESI) m/z 401.1 [M+H] ⁺

Compound 14: General procedure A according to variant ii) was used for its preparation in 51% yield from compound VI using n-propyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 7.60 (s, 1H), 7.56 - 7.48 (m, 2H), 6.40 (br t, J = 5.9 Hz, 1H), 5.98 (br t, J = 5.6 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.33 - 4.26 (m, 3H), 3.00 - 2.94 (m, 2H), 2.93 - 2.89 (m, 1H), 2.60 (br d, J = 15.7 Hz, 1H), 2.39 (br dd, MS (ESI) m/z 359.2 [M+H] ⁺

Compound 15: General procedure A according to variant ii) was used for its preparation in 54% yield from compound VI using ethyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (s, 1H), 7.60 (s, 1H), 7.56 - 7.52 (m, 1H), 7.51 - 7.47 (m, 1H), 6.41 (t, J = 6.1 Hz, 1H), 5.93 (t, J = 5.6 Hz, 1H), 5.10 (dd, J = 5.1, 13.3 Hz, 1H), 4.46 - 4.38 (m, 1H), 4.34 - 4.25 (m, 3H), 3.03 (dq, J = 5.7, 7.1 Hz, 2H), 2.91 (ddd, J = 5.4, 13.7, 17.5 MS (ESI) m/z 345.3 [M+H] ⁺

Compound 16: For its preparation, general procedure A according to variant ii) was used in 31% yield from compound VI using 4-ethoxy-phenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (br s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 7.65 (s, 1H), 7.55 (d, J = 1.0 Hz, 2H), 7.33 - 7.26 (m, 2H), 6.82 - 6.76 (m, 2H), 6.64 (br d, J = 3.3 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.34 (m, 3H), 4.33 - 4.26 (m, 1H), 3.94 (q, J = 6.9 Hz, 2H), 2.97 - 2.85 (m, 1H), 2.59 (td, J = 2.0, 15.3 Hz, 1H), 2.45 - 2.36 (m, 1H), 2.05 - 1.95 (m, 1H), 1.29 (t, J = 7.0 Hz, 3H). MS (ESI) m/z 437.3 [M+H] ⁺

Compound 17: General procedure A according to variant ii) was used for its preparation in 59% yield from compound VI using 2-methoxy-5-methylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (s, 1H), 7.98 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.65 (s, 1H), 7.56 (s, 2H), 7.40 (br t, J = 5.9 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.67 (dd, J = 1.5, 8.3 Hz, 1H), 5.11 (dd, J = 5.0, 13.3 Hz, 1H), 4.48 - 4.36 (m, 3H), 4.35 - 4.26 (m, 1H), 3.79 (s, 3H), 2.97 - 2.85 (m, 1H), 2.64 - 2.56 (m, 1H), 2.39 (br dd, J = 4.3, 13.1 Hz, 1H), 2.19 (s, 3H), 2.04 - 1.96 (m, 1H). MS (ESI) m/z 437.3 [M+H] ⁺

Compound 18: General procedure A according to variant ii) was used for its preparation in 11% yield from compound VI using 4-ethylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.50 (s, 1H), 7.66 (s, 1H), 7.56 (s, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.05 (br d, J = 8.4 Hz, 2H), 6.67 (br t, J = 5.9 Hz, 1H), 5.11 (dd, J = 4.9, 13.2 Hz, 1H), 4.47 - 4.36 (m, 3H), 4.34 - 4.26 (m, 1H), 2.97 - 2.83 (m, 1H), 2.64 - 2.53 (m, 3H), 2.39 (br dd, J = 4.4, 13.3 Hz, 1H), 2.06 - 1.94 (m, 1H), 1.13 (t, J = 7.6 Hz, 3H). MS (ESI) m/z 421.3 [M+H] ⁺

Compound 19: For its preparation, general procedure A according to variant ii) was used in 10% yield from compound VI using 3-chloro-2-methylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (br s, 1H), 8.02 (s, 1H), 7.74 (br d, J = 7.4 Hz, 1H), 7.68 (s, 1H), 7.57 (s, 2H), 7.16 - 7.05 (m, 3H), 5.12 (br dd, J = 4.5, 13.1 Hz, 1H), 4.50 - 4.38 (m, 3H), 4.35 - 4.27 (m, 1H), 2.99 - 2.82 (m, 1H), 2.62 (br s, 1H), 2.39 (br s, 1H), 2.24 (s, 3H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 441.2 [M+H] ⁺

Compound 20: General procedure A according to variant ii) was used for its preparation in 26% yield from compound VI using 3,5-dimethylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (br s, 1H), 8.43 (s, 1H), 7.66 (s, 1H), 7.56 (s, 2H), 7.03 (s, 2H), 6.69 (br t, J = 5.9 Hz, 1H), 6.54 (s, 1H), 5.11 (dd, J = 5.0, 13.3 Hz, 1H), 4.47 - 4.36 (m, 3H), 4.34 - 4.27 (m, 1H), 2.97 - 2.85 (m, 1H), 2.59 (br dd, J = 2.1, 15.3 Hz, 1H), 2.45 - 2.36 (m, 1H), 2.19 (s, 6H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 421.3 [M+H] ⁺

Compound 21: General procedure A according to variant ii) was used for its preparation in 5% yield from compound VI using 4-methylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (s, 1H), 8.47 (s, 1H), 7.66 (s, 1H), 7.56 (s, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.2 Hz, 2H), 6.67 (t, J = 6.0 Hz, 1H), 5.11 (dd, J = 5.0, 13.3 Hz, 1H), 4.46 - 4.36 (m, 3H), 4.34 - 4.27 (m, 1H), 2.97 - 2.85 (m, 1H), 2.63 - 2.56 (m, 1H), 2.46 - 2.35 (m, 1H), 2.21 (s, 3H), 2.06 - 1.95 (m, 1H). MS (ESI) m/z 407.3 [M+H] ⁺

Compound 22: General procedure A according to variant ii) was used for its preparation in 49% yield from compound VI using 2-ethoxyphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.04 (br d, J = 7.3 Hz, 1H), 7.65 (s, 1H), 7.57 (s, 2H), 6.96 - 6.91 (m, 1H), 6.89 - 6.79 (m, 2H), 5.07 (br dd, J = 4.5, 13.4 Hz, 1H), 4.49 - 4.36 (m, 3H), 4.35 - 4.26 (m, 1H), 4.06 (q, J = 6.9 Hz, 2H), 2.95 - 2.82 (m, 1H), 2.65 - 2.57 (m, 1H), 2.45 - 2.35 (m, 1H), 2.06 - 1.94 (m, 1H), 1.36 (t, J = 7.0 Hz, 3H). MS (ESI) m/z 437.2 [M+H] ⁺

Compound 23: Its preparation used general procedure A according to variant ii) in 47% yield from compound VI using 4-methoxy-2-methylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 7.65 (br d, J = 13.2 Hz, 2H), 7.56 (s, 2H), 7.47 (br d, J = 8.7 Hz, 1H), 6.84 (br t, J = 5.5 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.68 (dd, J = 2.7, 8.7 Hz, 1H), 5.11 (br dd, J = 5.0, 13.2 Hz, 1H), 4.49 - 4.36 (m, 3H), 4.34 - 4.27 (m, 1H), 3.69 (s, 3H), 2.98 - 2.84 (m, 1H), 2.60 (br d, J = 17.5 Hz, 1H), 2.46 - 2.36 (m, 1H), 2.16 (s, 3H), 2.05 - 1.92 (m, 1H). MS (ESI) m/z 437.3 [M+H] ⁺

Compound 24: General procedure A according to variant ii) was used for its preparation in 24% yield from compound VI using benzyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (s, 1H), 7.64 (s, 1H), 7.56 - 7.48 (m, 2H), 7.33 - 7.18 (m, 5H), 6.57 (br t, J = 6.1 Hz, 1H), 6.51 (br t, J = 5.9 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.39 (m, 1H), 4.36 - 4.26 (m, 3H), 4.24 (d, J = 6.0 Hz, 2H), 2.97 - 2.86 (m, 1H), 2.64 - 2.56 (m, 1H), 2.46 - 2.36 (m, 1H), 2.05 - 1.96 (m, 1H). MS (ESI) m/z 407.1 [M+H] ⁺

Compound 25: General procedure A according to variant ii) was used for its preparation in 51% yield from compound VI using 2,6-dimethylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.55 (s, 2H), 7.07 - 6.99 (m, 3H), 6.65 (br s, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.39 - 4.27 (m, 3H), 2.96 - 2.86 (m, 1H), 2.60 (br dd, J = 2.1, 15.3 Hz, 1H), 2.41 (dt, J = 4.4, 13.2 Hz, 1H), 2.17 (s, 6H), 2.06 - 1.95 (m, 1H). MS (ESI) m/z 421.3 [M+H] ⁺

Compound 26: General procedure A according to variant ii) was used for its preparation in 17% yield from compound VI using methylcyclopropyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 7.61 (s, 1H), 7.56 - 7.47 (m, 2H), 6.43 (br t, J = 5.9 Hz, 1H), 6.04 (br t, J = 5.6 Hz, 1H), 5.11 (dd, J = 5.0, 13.2 Hz, 1H), 4.47 - 4.37 (m, 1H), 4.35 - 4.25 (m, 3H), 2.90 (br t, J = 6.2 Hz, 3H), 2.60 (br d, J = 17.2 Hz, 1H), 2.39 (br dd, J = 4.3, 13.0 Hz, 1H), 2.05 - 1.95 (m, 1H), 0.93 - 0.82 (m, 1H), 0.42 - 0.33 (m, 2H), 0.13 (br d, J = 4.6 Hz, 2H). MS (ESI) m/z 371.3 [M+H] ⁺

Compound 27: General procedure A according to variant ii) was used for its preparation in 8% yield from compound VI using 2-phenylethyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 7.61 (s, 1H), 7.55 - 7.47 (m, 2H), 7.33 - 7.26 (m, 2H), 7.23 - 7.16 (m, 3H), 6.50 (br t, J = 5.9 Hz, 1H), 5.99 (br t, J = 5.6 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.34 - 4.26 (m, 3H), 3.25 (q, J = 6.8 Hz, 2H), 2.97 - 2.86 (m, 1H), 2.69 (t, J = 7.3 Hz, 2H), 2.60 (br d, J = 17.5 Hz, 1H), 2.39 (br dd, J = 4.4, 13.2 Hz, 1H), 2.04-1.96 (m, 1H). 421.2 [M+H] ⁺

Compound 28: General procedure A according to variant ii) was used for its preparation in 27% yield from compound VI using cyclopentyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 7.60 (s, 1H), 7.56 - 7.48 (m, 2H), 6.27 (br t, J = 6.0 Hz, 1H), 5.98 (d, J = 7.3 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.46 - 4.37 (m, 1H), 4.33 - 4.26 (m, 3H), 3.92 - 3.81 (m, 1H), 2.97 - 2.85 (m, 1H), 2.60 (br d, J = 17.6 Hz, 1H), 2.39 (br dd, J = 4.4, 13.1 Hz, 1H), 2.04 - 1.96 (m, 1H), 1.84 - 1.73 (m, 2H), 1.64 - 1.55 (m, 2H), 1.52 - 1.44 (m, 2H), 1.35 - 1.25 (m, 2H). MS (ESI) m/z 385.3 [M+H] ⁺

Compound 29: General procedure A according to variant ii) was used for its preparation in 45% yield from compound VI using cyclohexyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 7.60 (s, 1H), 7.56 - 7.47 (m, 2H), 6.30 (br t, J = 5.9 Hz, 1H), 5.89 (d, J = 8.1 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.47 - 4.37 (m, 1H), 4.33 - 4.25 (m, 3H), 3.44 - 3.35 (m, 1H), 2.98 - 2.85 (m, 1H), 2.60 (br d, J = 17.6 Hz, 1H), 2.45 - 2.37 (m, 1H), 2.05 - 1.94 (m, 1H), 1.81 - 1.71 (m, 2H), 1.69 - 1.59 (m, 2H), 1.57 - 1.47 (m, 1H), 1.32 - 1.19 (m, 2H), 1.18 - 1.04 (m, 3H). MS (ESI) m/z 399.3 [M+H] ⁺

Compound 30: General procedure A according to variant ii) was used for its preparation in 46% yield from compound VI using 5-chloro-2-methoxyphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (s, 1H), 8.22 (br d, J = 15.0 Hz, 2H), 7.66 (s, 1H), 7.61 - 7.48 (m, 3H), 7.01 - 6.95 (m, 1H), 6.94 - 6.87 (m, 1H), 5.12 (dd, J = 5.0, 13.2 Hz, 1H), 4.49 - 4.38 (m, 3H), 4.36 - 4.26 (m, 1H), 3.84 (s, 3H), 2.97 - 2.85 (m, 1H), 2.64 - 2.56 (m, 1H), 2.47 - 2.36 (m, 1H), 2.07 - 1.96 (m, 1H). MS (ESI) m/z 457.0 [M+H] ⁺

Compound 31: General procedure A according to variant ii) was used for its preparation in 43% yield from compound VI using 3-ethylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (s, 1H), 8.54 (s, 1H), 7.66 (s, 1H), 7.56 (s, 2H), 7.27 (s, 1H), 7.23 - 7.17 (m, 1H), 7.15 - 7.09 (m, 1H), 6.77 - 6.67 (m, 2H), 5.11 (br dd, J = 5.0, 13.2 Hz, 1H), 4.49 - 4.37 (m, 3H), 4.35 - 4.27 (m, 1H), 2.98 - 2.85 (m, 1H), 2.63 - 2.52 (m, 3H), 2.44 - 2.36 (m, 1H), 2.05 - 1.94 (m, 1H), 1.15 (t, J = 7.6 Hz, 3H). MS (ESI) m/z 421.0 [M+H] ⁺

Compound 32: For its preparation general procedure A according to variant ii) was used in 67% yield from compound VI using 4-chloro-2-methylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (br s, 1H), 7.91 - 7.83 (m, 2H), 7.68 (s, 1H), 7.57 (s, 2H), 7.21 (d, J = 2.3 Hz, 1H), 7.19 - 7.11 (m, 2H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.38 (m, 3H), 4.35 - 4.28 (m, 1H), 2.97 - 2.86 (m, 1H), 2.64 - 2.56 (m, 1H), 2.44 - 2.37 (m, 1H), 2.19 (s, 3H), 2.05 - 1.97 (m, 1H). MS (ESI) m/z 441.0 [M+H] ⁺

Compound 33: For its preparation, general procedure A according to variant ii) was used in 21% yield from compound VI using 3-chloro-2-fluorophenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (s, 1H), 8.63 (br s, 1H), 8.15 - 8.04 (m, 1H), 7.67 (s, 1H), 7.57 (s, 2H), 7.23 (br t, J = 5.7 Hz, 1H), 7.16 - 7.05 (m, 2H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.50 - 4.38 (m, 3H), 4.37 - 4.26 (m, 1H), 2.97 - 2.85 (m, 1H), 2.60 (br d, J = 17.4 Hz, 1H), 2.40 (br dd, J = 4.3, 13.2 Hz, 1H), 2.05 - 1.96 (m, 1H). MS (ESI) m/z 444.9 [M+H] ⁺

Compound 34: General procedure A according to variant ii) was used for its preparation in 22% yield from compound VI using 3-fluorophenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (s, 1H), 8.87 (s, 1H), 7.66 (s, 1H), 7.56 (d, J = 0.7 Hz, 2H), 7.45 (td, J = 2.3, 12.2 Hz, 1H), 7.29 - 7.20 (m, 1H), 7.06 (dd, J = 1.2, 8.1 Hz, 1H), 6.83 (t, J = 5.9 Hz, 1H), 6.70 (dt, J = 2.0, 8.5 Hz, 1H), 5.11 (dd, J = 5.0, 13.2 Hz, 1H), 4.48 - 4.38 (m, 3H), 4.35 - 4.27 (m, 1H), 2.97 - 2.85 (m, 1H), 2.59 (br dd, J = 2.1, 15.5 Hz, 1H), 2.39 (br dd, J = 4.4, 13.0 Hz, 1H), 2.04 - 1.96 (m, 1H). MS (ESI) m/z 411.0 [M+H] ⁺

Compound 35: General procedure A according to variant ii) was used for its preparation in 14% yield from compound VI using 2,5-dichlorophenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (br s, 1H), 8.32 (s, 2H), 7.74 - 7.64 (m, 2H), 7.58 (s, 2H), 7.44 (d, J = 8.6 Hz, 1H), 7.02 (dd, J = 2.4, 8.6 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.49 - 4.40 (m, 3H), 4.37 - 4.27 (m, 1H), 2.97 - 2.85 (m, 1H), 2.60 (br d, J = 17.5 Hz, 1H), 2.40 (br dd, J = 4.2, 13.1 Hz, 1H), 2.07 - 1.95 (m, 1H). MS (ESI) m/z 460.9 [M+H] ⁺

Compound 36: General procedure A according to variant ii) was used for its preparation in 46% yield from compound VI using 2-ethylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (br s, 1H), 7.76 (br d, J = 6.7 Hz, 2H), 7.68 (s, 1H), 7.57 (s, 2H), 7.17 - 7.06 (m, 3H), 6.94 (dt, J = 1.1, 7.4 Hz, 1H), 5.12 (dd, J = 5.1, 13.2 Hz, 1H), 4.48 - 4.37 (m, 3H), 4.35 - 4.26 (m, 1H), 2.96 - 2.85 (m, 1H), 2.64 - 2.58 (m, 1H), 2.58 - 2.53 (m, 2H), 2.46 - 2.37 (m, 1H), 2.05 - 1.95 (m, 1H), 1.14 (t, J = 7.5 Hz, 3H). MS (ESI) m/z 421.3 [M+H] ⁺

Compound 37: General procedure A according to variant ii) was used for its preparation in 42% yield from compound VI using 2-methylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (br s, 1H), 7.84 - 7.76 (m, 2H), 7.69 (s, 1H), 7.57 (s, 2H), 7.16 - 7.05 (m, 3H), 6.88 (dt, J = 0.9, 7.4 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.49 - 4.38 (m, 3H), 4.36 - 4.26 (m, 1H), 2.98 - 2.85 (m, 1H), 2.64 - 2.55 (m, 1H), 2.47 - 2.36 (m, 1H), 2.19 (s, 3H), 2.05 - 1.96 (m, 1H). MS (ESI) m/z 407.3 [M+H] ⁺

Compound 38: General procedure A according to variant ii) was used for its preparation in 30% yield from compound VI using 3,5-dichlorophenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (br s, 1H), 9.13 (s, 1H), 7.66 (s, 1H), 7.56 (d, J = 0.7 Hz, 2H), 7.50 (d, J = 1.8 Hz, 2H), 7.07 (br d, J = 1.7 Hz, 2H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.36 (m, 3H), 4.35 - 4.27 (m, 1H), 2.97 - 2.83 (m, 1H), 2.64 - 2.56 (m, 1H), 2.45 - 2.37 (m, 1H), 2.04 - 1.96 (m, 1H). MS (ESI) m/z 461.2 [M+H] ⁺

Compound 39: for its preparation general procedure A according to variant ii) was used in 29% yield from compound VI using 3,4-difluorophenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (s, 1H), 8.90 (s, 1H), 7.66 (s, 1H), 7.62 (dt, J = 2.6, 6.8 Hz, 1H), 7.56 (d, J = 0.9 Hz, 2H), 7.33 - 7.22 (m, 1H), 7.09 - 7.03 (m, 1H), 6.93 - 6.82 (m, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.37 (m, 3H), 4.34 - 4.26 (m, 1H), 2.98 - 2.85 (m, 1H), 2.64 - 2.56 (m, 1H), 2.46 - 2.36 (m, 1H), 2.04 - 1.95 (m, 1H). MS (ESI) m/z 429.2 [M+H] ⁺

Compound 40: General procedure A according to variant ii) was used for its preparation in 69% yield from compound VI using 1,2,3,4-tetrahydronaphth-1-yl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 7.65 (s, 1H), 7.57 - 7.51 (m, 2H), 7.26 - 7.20 (m, 1H), 7.17 - 7.11 (m, 2H), 7.09 - 7.03 (m, 1H), 6.41 - 6.29 (m, 2H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.85 - 4.77 (m, 1H), 4.47 - 4.40 (m, 1H), 4.39 - 4.28 (m, 3H), 2.97 - 2.85 (m, 1H), 2.77 - 2.66 (m, 2H), 2.64 - 2.57 (m, 1H), 2.40 (dd, J = 4.6, 13.1 Hz, 1H), 2.06 - 1.97 (m, 1H), 1.92 - 1.64 (m, 4H). MS (ESI) m/z 447.3 [M+H] ⁺

Compound 41: For its preparation, general procedure A according to variant ii) was used in 16% yield from compound VI using 4-trifluoromethylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 9.26 - 9.05 (m, 1H), 7.70 - 7.61 (m, 3H), 7.61 - 7.54 (m, 4H), 7.00 (br d, J = 6.1 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.52 - 4.38 (m, 3H), 4.37 - 4.27 (m, 1H), 2.92 (ddd, J = 5.4, 13.6, 17.4 Hz, 1H), 2.65 - 2.57 (m, 1H), 2.47 - 2.36 (m, 1H), 2.10 - 1.95 (m, 1H). MS (ESI) m/z 461.0 [M+H] ⁺

Compound 42: General procedure A according to variant ii) was used for its preparation in 26% yield from compound VI using 3-chloro-4-fluorophenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (s, 1H), 8.85 (s, 1H), 7.80 - 7.72 (m, 1H), 7.66 (s, 1H), 7.56 (d, J = 0.9 Hz, 2H), 7.31 - 7.21 (m, 2H), 6.86 (t, J = 5.9 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.49 - 4.37 (m, 3H), 4.35 - 4.26 (m, 1H), 2.98 - 2.84 (m, 1H), 2.60 (br d, J = 17.6 Hz, 1H), 2.45 - 2.36 (m, 1H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 445.2 [M+H] ⁺

Compound 43: General procedure A according to variant ii) was used for its preparation in 42% yield from compound VI using 3-methylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (br s, 1H), 8.62 - 8.50 (m, 1H), 7.66 (s, 1H), 7.56 (s, 2H), 7.25 (s, 1H), 7.18 (br d, J = 8.3 Hz, 1H), 7.14 - 7.05 (m, 1H), 6.81 - 6.68 (m, 2H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.49 - 4.36 (m, 3H), 4.35 - 4.26 (m, 1H), 2.97 - 2.85 (m, 1H), 2.64 - 2.56 (m, 1H), 2.45 - 2.36 (m, 1H), 2.24 (s, 3H), 2.06 - 1.95 (m, 1H). MS (ESI) m/z 407.2 [M+H] ⁺

Compound 44: General procedure A according to variant ii) was used for its preparation in 53% yield from compound VI using 2,3-dimethylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (s, 1H), 7.80 (s, 1H), 7.68 (s, 1H), 7.57 (s, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.03 - 6.94 (m, 2H), 6.84 (d, J = 7.2 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.49 - 4.37 (m, 3H), 4.36 - 4.27 (m, 1H), 2.98 - 2.85 (m, 1H), 2.64 - 2.57 (m, 1H), 2.46 - 2.37 (m, 1H), 2.23 (s, 3H), 2.08 (s, 3H), 2.04 - 1.97 (m, 1H). MS (ESI) m/z 421.3 [M+H] ⁺

Compound 45: General procedure A according to variant ii) was used for its preparation in 29% yield from compound VI using 2,4-dichlorophenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (s, 1H), 8.26 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.68 (s, 1H), 7.58 (s, 3H), 7.56 (d, J = 2.4 Hz, 1H), 7.32 (dd, J = 2.5, 9.0 Hz, 1H), 5.11 (dd, J = 5.1, 13.4 Hz, 1H), 4.51 - 4.40 (m, 3H), 4.37 - 4.27 (m, 1H), 2.98 - 2.85 (m, 1H), 2.64 - 2.56 (m, 1H), 2.46 - 2.37 (m, 1H), 2.06 - 1.97 (m, 1H). MS (ESI) m/z 460.9 [M+H] ⁺

Compound 46: General procedure A according to variant ii) was used for its preparation in 42% yield from compound VI using 3,4-dichlorophenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 9.08 (br s, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.66 (s, 1H), 7.56 (s, 2H), 7.45 (d, J = 8.8 Hz, 1H), 7.28 (dd, J = 2.4, 8.8 Hz, 1H), 7.02 (br d, J = 5.7 Hz, 1H), 5.11 (dd, J = 5.0, 13.3 Hz, 1H), 4.48 - 4.36 (m, 3H), 4.34 - 4.27 (m, 1H), 2.97 - 2.85 (m, 1H), 2.59 (br d, J = 17.6 Hz, 1H), 2.42 - 2.38 (m, 1H), 2.04 - 1.96 (m, 1H). MS (ESI) m/z 460.9 [M+H] ⁺

Compound 47: General procedure A according to variant ii) was used for its preparation in 32% yield from compound VI using 3-trifluoromethylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 9.08 (s, 1H), 7.98 (s, 1H), 7.67 (s, 1H), 7.57 (s, 2H), 7.54 (br d, J = 8.8 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 6.95 (br t, J = 5.9 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.37 (m, 3H), 4.35 - 4.26 (m, 1H), 2.98 - 2.84 (m, 1H), 2.59 (br d, J = 17.5 Hz, 1H), 2.39 (br dd, J = 4.5, 13.1 Hz, 1H), 2.04 - 1.95 (m, 1H). MS (ESI) m/z 461.2 [M+H] ⁺

Compound 48: General procedure A according to variant ii) was used for its preparation in 20% yield from compound VI using 2-fluorophenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 8.47 (br s, 1H), 8.16 - 8.08 (m, 1H), 7.66 (s, 1H), 7.57 (s, 2H), 7.24 - 7.14 (m, 2H), 7.08 (t, J = 7.6 Hz, 1H), 6.97 - 6.90 (m, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.50 - 4.38 (m, 3H), 4.36 - 4.25 (m, 1H), 2.98 - 2.84 (m, 1H), 2.62 - 2.57 (m, 1H), 2.44 - 2.36 (m, 1H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 411.2 [M+H] ⁺

Compound 49: for its preparation general procedure A according to variant ii) was used in 14% yield from compound VI using 2-trifluoromethylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 8.00 - 7.90 (m, 2H), 7.68 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.60 - 7.55 (m, 4H), 7.20 (t, J = 7.6 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.49 - 4.39 (m, 3H), 4.35 - 4.27 (m, 1H), 2.97 - 2.85 (m, 1H), 2.64 - 2.56 (m, 1H), 2.42 - 2.37 (m, 1H), 2.05 - 1.96 (m, 1H). MS (ESI) m/z 461.2 [M+H] ⁺

Compound 50: For its preparation, general procedure A according to variant ii) was used in 41% yield from compound VI using 2,3-dichlorophenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (s, 1H), 8.33 (s, 1H), 8.16 (dd, J = 1.5, 8.2 Hz, 1H), 7.72 - 7.60 (m, 2H), 7.58 (s, 2H), 7.32 - 7.16 (m, 2H), 5.12 (dd, J = 5.0, 13.2 Hz, 1H), 4.50 - 4.37 (m, 3H), 4.36 - 4.28 (m, 1H), 2.97 - 2.85 (m, 1H), 2.60 (br dd, J = 2.1, 15.5 Hz, 1H), 2.40 (br dd, J = 4.5, 13.1 Hz, 1H), 2.05 - 1.94 (m, 1H). MS (ESI) m/z 461.1 [M+H] ⁺

Compound 51: Its preparation used general procedure A according to variant ii) in 35% yield from compound VI using 2-(4-methoxyphenyl)-ethyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 7.61 (s, 1H), 7.56 - 7.45 (m, 2H), 7.11 (br d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.49 (br t, J = 5.7 Hz, 1H), 5.96 (br t, J = 5.6 Hz, 1H), 5.11 (dd, J = 5.0, 13.3 Hz, 1H), 4.48 - 4.37 (m, 1H), 4.35 - 4.24 (m, 3H), 3.71 (s, 3H), 3.25 - 3.16 (m, 2H), 2.98 - 2.84 (m, 1H), 2.65 - 2.55 (m, 3H), 2.39 (br dd, J = 4.3, 13.0 Hz, 1H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 451.0 [M+H] ⁺

Compound 52: General procedure A according to variant ii) was used for its preparation in 35% yield from compound VI using 4-methoxyphenylmethyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 7.63 (s, 1H), 7.57 - 7.47 (m, 2H), 7.17 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.52 (br t, J = 6.0 Hz, 1H), 6.42 (br t, J = 5.9 Hz, 1H), 5.12 (dd, J = 5.0, 13.3 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.36 - 4.26 (m, 3H), 4.16 (d, J = 5.9 Hz, 2H), 3.72 (s, 3H), 2.98 - 2.84 (m, 1H), 2.64 - 2.56 (m, 1H), 2.44 - 2.36 (m, 1H), 2.05 - 1.94 (m, 1H). MS (ESI) m/z 437.3 [M+H] ⁺

Compound 53: General procedure A according to variant ii) was used for its preparation in 35% yield from compound VI using 3-methoxyphenylmethyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 7.64 (s, 1H), 7.57 - 7.47 (m, 2H), 7.22 (t, J = 7.8 Hz, 1H), 6.86 - 6.75 (m, 3H), 6.58 (br t, J = 6.1 Hz, 1H), 6.50 (br t, J = 6.0 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.49 - 4.38 (m, 1H), 4.36 - 4.26 (m, 3H), 4.21 (d, J = 5.9 Hz, 2H), 3.71 (s, 3H), 2.98 - 2.85 (m, 1H), 2.64 - 2.56 (m, 1H), 2.40 (br dd, J = 4.4, 13.1 Hz, 1H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 437.3 [M+H] ⁺

Compound 54: General procedure A according to variant ii) was used for its preparation in 36% yield from compound VI using (R)-1-phenylethyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 7.61 (s, 1H), 7.55 - 7.45 (m, 2H), 7.34 - 7.27 (m, 4H), 7.20 (dt, J = 2.6, 5.7 Hz, 1H), 6.50 (d, J = 8.1 Hz, 1H), 6.41 (br t, J = 5.9 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.76 (quin, J = 7.3 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.34 - 4.25 (m, 3H), 2.98 - 2.85 (m, 1H), 2.63 - 2.56 (m, 1H), 2.39 (br dd, J = 4.5, 13.2 Hz, 1H), 2.05 - 1.95 (m, 1H), 1.33 (d, J = 7.0 Hz, 3H). MS (ESI) m/z 421.0 [M+H] ⁺

Compound 55: For its preparation, general procedure A according to variant ii) was used in 34% yield from compound VI using (S)-1-phenylethyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 7.61 (s, 1H), 7.55 - 7.45 (m, 2H), 7.34 - 7.26 (m, 4H), 7.20 (dt, J = 2.7, 5.6 Hz, 1H), 6.50 (d, J = 8.1 Hz, 1H), 6.40 (br t, J = 5.9 Hz, 1H), 5.11 (dd, J = 5.0, 13.3 Hz, 1H), 4.76 (quin, J = 7.2 Hz, 1H), 4.46 - 4.38 (m, 1H), 4.35 - 4.23 (m, 3H), 2.98 - 2.85 (m, 1H), 2.60 (br d, J = 17.6 Hz, 1H), 2.39 (br dd, J = 4.4, 13.1 Hz, 1H), 2.05 - 1.95 (m, 1H), 1.33 (d, J = 7.0 Hz, 3H). MS (ESI) m/z 421.0 [M+H] ⁺

Compound 56: For its preparation general procedure A according to variant ii) was used in 35% yield from compound VI using 4-tert-butylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.52 (s, 1H), 7.66 (s, 1H), 7.56 (d, J = 0.9 Hz, 2H), 7.34 - 7.27 (m, 2H), 7.26 - 7.20 (m, 2H), 6.68 (t, J = 6.0 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.34 (m, 3H), 4.34 - 4.26 (m, 1H), 2.96 - 2.84 (m, 1H), 2.59 (td, J = 1.9, 15.4 Hz, 1H), 2.43 - 2.36 (m, 1H), 2.04 - 1.94 (m, 1H), 2.04 - 1.94 (m, 1H), 1.24 (s, 9H). MS (ESI) m/z 449.3 [M+H] ⁺

Compound 57: General procedure A according to variant ii) was used for its preparation in 74% yield from compound VI using 4-iso-propylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.50 (s, 1H), 7.66 (s, 1H), 7.56 (s, 2H), 7.31 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 6.67 (br t, J = 5.9 Hz, 1H), 5.11 (dd, J = 5.0, 13.3 Hz, 1H), 4.52 - 4.37 (m, 3H), 4.35 - 4.25 (m, 1H), 2.97 - 2.85 (m, 1H), 2.84 - 2.74 (m, 1H), 2.59 (br MS (ESI) m/z 435.3 [M+H] ⁺

Compound 58: General procedure A according to variant ii) was used for its preparation in 75% yield from compound VI using cyclohexylmethyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 7.60 (s, 1H), 7.51 (q, J = 7.7 Hz, 2H), 6.36 (br t, J = 6.1 Hz, 1H), 6.00 (t, J = 5.7 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.37 (m, 1H), 4.34 - 4.25 (m, 3H), 2.98 - 2.83 (m, 3H), 2.63 - 2.56 (m, 1H), 2.44 - 2.36 (m, 1H), 2.06 - 1.92 (m, 1H), 1.74 - 1.56 (m, 5H), 1.42 - 1.25 (m, 1H), 1.24 - 1.07 (m, 3H), 0.91 - 0.78 (m, 2H). MS (ESI) m/z 413.3 [M+H] ⁺

Compound 59: For its preparation, general procedure A according to variant ii) was used in 23% yield from compound VI using 3-chloro-4-methoxyphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (br s, 1H), 8.73 - 8.59 (m, 1H), 7.68 - 7.60 (m, 2H), 7.56 (s, 2H), 7.21 (dd, J = 2.3, 8.9 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.80 (br d, J = 3.4 Hz, 1H), 5.11 (dd, J = 5.0, 13.3 Hz, 1H), 4.49 - 4.35 (m, 3H), 4.34 - 4.26 (m, 1H), 3.78 (s, 3H), 2.97 - 2.84 (m, MS (ESI) m/z 457.2 [M+H] ⁺

Compound 60: General procedure A according to variant ii) was used for its preparation in 9% yield from compound VI using 2-methoxyphenylmethyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (br s, 1H), 7.63 (s, 1H), 7.57 - 7.48 (m, 2H), 7.25 - 7.15 (m, 2H), 6.96 (d, J = 8.1 Hz, 1H), 6.90 (t, J = 7.3 Hz, 1H), 6.60 (t, J = 6.0 Hz, 1H), 6.31 (t, J = 5.9 Hz, 1H), 5.12 (dd, J = 5.1, 13.4 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.36 - 4.26 (m, 3H), 4.19 (d, J = 6.0 Hz, 2H), 3.80 (s, 3H), 3.01 - 2.83 (m, 1H), 2.60 (br d, J = 17.6 Hz, 1H), 2.40 (br dd, J = 4.4, 13.1 Hz, 1H), 2.04 - 1.96 (m, 1H). MS (ESI) m/z 437.3 [M+H] ⁺

Compound 61: Its preparation used general procedure A according to variant ii) in 72% yield from compound VI using 4-chloro-3-methylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.71 (s, 1H), 7.66 (s, 1H), 7.56 (s, 2H), 7.40 (d, J = 1.8 Hz, 1H), 7.30 - 7.25 (m, 1H), 7.24 - 7.19 (m, 1H), 6.87 - 6.75 (m, 1H), 5.11 (dd, J = 5.0, 13.3 Hz, 1H), 4.48 - 4.35 (m, 3H), 4.34 - 4.25 (m, 1H), 2.98 - 2.84 (m, 1H), 2.60 (br dd, J = 1.6, 17.4 Hz, 1H), 2.46 - 2.36 (m, 1H), 2.26 (s, 3H), 2.06 - 1.94 (m, 1H). MS (ESI) m/z 441.3 [M+H] ⁺

Compound 62: For its preparation, general procedure A according to variant ii) was used in 64% yield from compound VI using 5-fluoro-2-methylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 7.96 - 7.79 (m, 2H), 7.68 (s, 1H), 7.58 (s, 2H), 7.31 (t, J = 5.8 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.66 (dt, J = 2.8, 8.3 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.51 - 4.36 (m, 3H), 4.36 - 4.27 (m, 1H), 3.02 - 2.80 (m, 1H), 2.65 - 2.56 (m, 1H), 2.46 - 2.36 (m, 1H), 2.16 (s, 3H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 425.3 [M+H] ⁺

Compound 63: General procedure A according to variant ii) was used for its preparation in 56% yield from compound VI using 3-methylphenylmethyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 7.64 (s, 1H), 7.57 - 7.49 (m, 2H), 7.23 - 7.15 (m, 1H), 7.11 - 6.96 (m, 3H), 6.56 (br t, J = 5.9 Hz, 1H), 6.48 (br t, J = 5.9 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.39 (m, 1H), 4.36 - 4.27 (m, 3H), 4.20 (d, J = 6.0 Hz, 2H), 2.98 - 2.84 (m, 1H), 2.60 (br dd, J = 1.6, 17.4 Hz, 1H), 2.44 - 2.36 (m, 1H), 2.27 (s, 3H), 2.05 - 1.96 (m, 1H). MS (ESI) m/z 421.3 [M+H] ⁺

Compound 64: Its preparation used general procedure A according to variant ii) in 67% yield from compound VI using 2-(4-chlorophenyl)-ethyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 7.61 (s, 1H), 7.57 - 7.51 (m, 1H), 7.50 - 7.45 (m, 1H), 7.34 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.48 (br t, J = 6.0 Hz, 1H), 5.99 (t, J = 5.6 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.37 (m, 1H), 4.35 - 4.25 (m, 3H), 3.24 (q, J = 6.8 Hz, 2H), 2.98 - 2.85 (m, 1H), 2.69 (t, J = 7.0 Hz, 2H), 2.65 - 2.56 (m, 1H), 2.45 - 2.37 (m, 1H), 2.05 - 1.94 (m, 1H). MS (ESI) m/z 455.3 [M+H] ⁺

Compound 65: For its preparation, general procedure A according to variant ii) was used in 44% yield from compound VI using 4-trifluoromethoylphenylmethyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 7.71 - 7.62 (m, 3H), 7.56 - 7.50 (m, 2H), 7.47 (br d, J = 8.1 Hz, 2H), 6.74 - 6.60 (m, 2H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.39 (m, 1H), 4.37 - 4.27 (m, 5H), 2.99 - 2.85 (m, 1H), 2.65 - 2.56 (m, 1H), 2.45 - 2.36 (m, 1H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 475.3 [M+H] ⁺

Compound 66: For its preparation, general procedure A according to variant ii) was used in 72% yield from compound VI using 2-biphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d6) δ = 10.98 (s, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.63 (s, 1H), 7.58 - 7.54 (m, 1H), 7.53 - 7.46 (m, 4H), 7.42 - 7.34 (m, 3H), 7.31 - 7.25 (m, 1H), 7.17 (dd, J = 1.4, 7.5 Hz, 1H), 7.15 - 7.06 (m, 2H), 5.12 (dd, J = 5.0, 13.3 Hz, 1H), 4.49 - 4.39 (m, 1H), 4.38 - 4.26 (m, 3H), 2.98 - 2.85 (m, 1H), 2.64 - 2.56 (m, 1H), 2.40 (br dd, J = 4.5, 13.1 Hz, 1H), 2.05 - 1.94 (m, 1H). MS (ESI) m/z 469.3 [M+H] ⁺

Compound 67: General procedure A according to variant ii) was used for its preparation in 51% yield from compound VI using 2-fluoro-5-methylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.36 (d, J = 2.1 Hz, 1H), 7.95 (dd, J = 1.6, 7.9 Hz, 1H), 7.66 (s, 1H), 7.57 (s, 2H), 7.16 (t, J = 5.8 Hz, 1H), 7.04 (dd, J = 8.3, 11.5 Hz, 1H), 6.77 - 6.67 (m, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.39 (m, 3H), 4.35 - 4.28 (m, 1H), 2.97 - 2.86 (m, 1H), 2.64 - 2.56 (m, 1H), 2.39 (dq, J = 5.0, 13.4 Hz, 1H), 2.23 (s, 3H), 2.04 - 1.96 (m, 1H). MS (ESI) m/z 425.0 [M+H] ⁺

Compound 68: General procedure A according to variant ii) was used for its preparation in 38% yield from compound VI using 3,4-dimethylphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.40 (s, 1H), 7.65 (s, 1H), 7.56 (s, 2H), 7.18 (s, 1H), 7.11 (dd, J = 2.0, 8.0 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.66 (t, J = 5.9 Hz, 1H), 5.11 (dd, J = 5.0, 13.2 Hz, 1H), 4.49 - 4.26 (m, 4H), 2.96 - 2.86 (m, 1H), 2.63 - 2.56 (m, 1H), 2.45 - 2.33 (m, 1H), 2.15 (s, 3H), 2.12 (s, 3H), 2.04 - 1.96 (m, 1H). MS (ESI) m/z 421.0 [M+H] ⁺

Compound 69: For its preparation, general procedure A according to variant ii) was used in 18% yield from compound VI using 2,5-difluorophenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.69 (br s, 1H), 8.02 (ddd, J = 3.2, 6.6, 11.3 Hz, 1H), 7.66 (s, 1H), 7.57 (s, 2H), 7.34 - 7.18 (m, 2H), 6.83 - 6.67 (m, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.49 - 4.39 (m, 3H), 4.36 - 4.27 (m, 1H), 2.98 - 2.85 (m, 1H), 2.64 - 2.56 (m, 1H), 2.45 - 2.34 (m, 1H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 429.0 [M+H] ⁺

Compound 70: General procedure A according to variant ii) was used for its preparation in 36% yield from compound VI using 3-phenyl-n-propyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 7.62 (s, 1H), 7.56 - 7.47 (m, 2H), 7.31 - 7.24 (m, 2H), 7.22 - 7.12 (m, 3H), 6.44 (br t, J = 6.1 Hz, 1H), 6.07 (t, J = 5.6 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.46 - 4.38 (m, 1H), 4.35 - 4.25 (m, 3H), 3.02 (q, J = 6.6 Hz, 2H), 2.96 - 2.86 (m, MS (ESI) m/z 435.0 [M+H] ⁺

Compound 71: For its preparation, general procedure A according to variant ii) was used in 23% yield from compound VI using 4-biphenyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.77 (s, 1H), 7.68 (s, 1H), 7.63 - 7.49 (m, 8H), 7.42 (t, J = 7.7 Hz, 2H), 7.32 - 7.27 (m, 1H), 6.82 (br t, J = 5.9 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.50 - 4.37 (m, 3H), 4.35 - 4.27 (m, 1H), 2.97 - 2.85 (m, 1H), 2.64 - 2.57 (m, 1H), 2.45 - 2.34 (m, 1H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 469.0 [M+H] ⁺

Compound 72: General procedure A according to variant ii) was used for its preparation in 58% yield from compound VI using 2-methoxyethyl-isocyanate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.96 (br s, 1H), 7.60 (s, 1H), 7.56 - 7.45 (m, 2H), 6.52 (br t, J = 5.7 Hz, 1H), 6.05 (br t, J = 5.3 Hz, 1H), 5.11 (br dd, J = 5.0, 13.2 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.35 - 4.25 (m, 3H), 3.32 - 3.31 (m, 2H), 3.25 (s, 3H), 3.18 (q, J = 5.5 Hz, 2H), 2.97 - 2.85 (m, 1H), 2.63 - 2.56 (m, 1H), 2.45 - 2.33 (m, 1H), 2.05 - 1.94 (m, 1H). MS (ESI) m/z 375.0 [M+H] ⁺ .

Compound 73: The general procedure according to variant ii) was used for its preparation in 40% yield from compound VI using 3-isocyanatobenzonitrile. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 9.10 (s, 1H), 7.95 (t, J = 1.7 Hz, 1H), 7.67 (s, 1H), 7.64 - 7.59 (m, 1H), 7.56 (s, 2H), 7.43 (t, J = 7.9 Hz, 1H), 7.34 (td, J = 1.2, 7.7 Hz, 1H), 7.04 (br t, J = 5.9 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.37 (m, 3H), 4.34 - 4.27 (m, 1H), 2.97 - 2.84 (m, 1H), 2.62 - 2.57 (m, 1H), 2.43 - 2.29 (m, 1H), 2.05 - 1.94 (m, 1H).
MS (ESI) m/z 418.2 [M+H] ⁺

Compound 74: The general procedure according to variant ii) was used for its preparation in 44% yield from compound VI using 4-isocyanatobenzonitrile. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (br s, 1H), 9.23 (s, 1H), 7.70 - 7.63 (m, 3H), 7.62 - 7.54 (m, 4H), 7.02 (t, J = 5.9 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.49 - 4.25 (m, 4H), 2.98 - 2.82 (m, 1H), 2.64 - 2.55 (m, 1H), 2.43 - 2.31 (m, 1H), 2.05 - 1.92 (m, 1H).
MS (ESI) m/z 418.2 [M+H] ⁺

Compound 75: For its preparation the general procedure according to variant ii) was used in 5% yield from compound VI using 1-(3-chloro-5-isocyanato-2-methylphenyl)-N,N-dimethylmethanamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (br s, 1H), 8.82 (s, 1H), 7.72 - 7.50 (m, 4H), 7.13 (d, J = 2.2 Hz, 1H), 6.83 (t, J = 5.9 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.52 - 4.25 (m, 4H), 3.30 (s, 2H), 2.98 - 2.84 (m, 1H), 2.65 - 2.56 (m, 1H), 2.43 - 2.32 (m, 1H), 2.25 (s, 3H), 2.14 (s, 6H), 2.05 - 1.95 (m, 1H).
MS (ESI) m/z 498.4 [M+H] ⁺
Scheme for the preparation of 1-(3-chloro-5-isocyanato-2-methylphenyl)-N,N-dimethylmethanamine:

Step 1: 3-chloro-2-methyl-5-nitrobenzoic acid. To a solution of 3-chloro-2-methylbenzoic acid (10.0 g, 58.6 mmol, 1.00 equiv.) in sulfuric acid (50.0 mL) was added nitric acid (4.19 g, 64.5 mmol, 2.99 mL, 1.10 equiv.) dropwise at -10°C. The mixture was then stirred at -10°C for 1 hour. The reaction mixture was poured into ice water (approximately 200 ml) and stirred, and the precipitated solid was collected by filtration and washed with water. 3-chloro-2-methyl-5-nitrobenzoic acid (16.0 g, crude) as a white solid was used in the next step without purification.

Step 2: (3-chloro-2-methyl-5-nitrophenyl)methanol. To a solution of 3-chloro-2-methyl-5-nitrobenzoic acid (14.0 g, 64.9 mmol, 1.00 equivalents) in tetrahydrofuran (100 mL) was added borane dimethyl sulfide complex (10.0 M, 13.0 mL, 2.00 equivalents) at 0°C. The mixture was then stirred at 25°C for 10 hours. The reaction mixture was quenched by adding methanol (15.0 mL) at 0°C, then filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain (3-chloro-2-methyl-5-nitrophenyl)methanol (12.0 g, 59.5 mmol, 92% yield) as a yellow solid.

Step 3: 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene. To a solution of (3-chloro-2-methyl-5-nitrophenyl)methanol (2.00 g, 9.92 mmol, 1.00 equivalents) in dichloromethane (20.0 mL) was added thionyl chloride (5.90 g, 49.6 mmol, 3.60 mL, 5.00 equivalents) at 0°C. The mixture was then stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene (2.20 g, crude) as a yellow oil.

Step 4: 1-(3-chloro-2-methyl-5-nitrophenyl)-N,N-dimethylmethanamine. To a solution of 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene (2.18 g, 9.92 mmol, 1.00 equivalents) and triethylamine (2.51 g, 24.8 mmol, 3.45 mL, 2.50 equivalents) in acetonitrile (20.0 mL) was added dimethylamine hydrochloride (1.01 g, 12.4 mmol, 1.25 equivalents). The mixture was then stirred at 25°C for 10 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 3/1) to give 1-(3-chloro-2-methyl-5-nitrophenyl)-N,N-dimethylmethanamine (0.450 g, 1.97 mmol, 20% yield) as a yellow oil.

Step 5: 3-chloro-5-((dimethylamino)methyl)-4-methylaniline. A mixture of 1-(3-chloro-2-methyl-5-nitrophenyl)-N,N-dimethylmethanamine (0.450 g, 1.97 mmol, 1.00 equiv.), ammonium chloride (105 mg, 1.97 mmol, 1.00 equiv.), and iron powder (549 mg, 9.84 mmol, 5.00 equiv.) in ethyl alcohol (6.00 mL) and water (3.00 mL) was stirred at 90°C for 10 hours. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (3 x 25.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 3-chloro-5-((dimethylamino)methyl)-4-methylaniline (0.400 g, 2.01 mmol, crude) as a yellow oil.

Step 6: 1-(3-chloro-5-isocyanato-2-methylphenyl)-N,N-dimethylmethanamine. A mixture of 3-chloro-5-((dimethylamino)methyl)-4-methylaniline (0.350 g, 1.76 mmol, 1.00 equiv.) and triphosgene (261 mg, 881 umol, 0.50 equiv.) in toluene (5.00 mL) was stirred at 110°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give 1-(3-chloro-5-isocyanato-2-methylphenyl)-N,N-dimethylmethanamine (0.450 g, crude, HCl) as a yellow solid.

Compound 76: The general procedure according to variant ii) was used for its preparation in 63% yield from compound VI using 1-chloro-5-isocyanato-4-methoxy-2-methylbenzene. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (s, 1H), 8.15 (s, 1H), 8.12 (s, 1H), 7.64 (s, 1H), 7.59 - 7.51 (m, 2H), 7.43 (t, J = 5.9 Hz, 1H), 6.95 (s, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.22 (m, 4H), 3.83 (s, 3H), 2.96 - 2.82 (m, 1H), 2.62 - 2.54 (m, 1H), 2.38 (br dd, J = 4.5, 12.9 Hz, 1H), 2.24 (s, 3H), 2.05 - 1.91 (m, 1H).
MS (ESI) m/z 471.2 [M+H] ⁺
Scheme for the preparation of 1-chloro-5-isocyanato-4-methoxy-2-methylbenzene:

Step 1: 1-Chloro-4-methoxy-2-methyl-5-nitrobenzene. To a solution of 4-chloro-5-methyl-2-nitrophenol (4.60 g, 24.5 mmol, 1.00 equiv.) in acetonitrile (50.0 mL) was added dimethyl sulfate (3.71 g, 29.4 mmol, 2.79 mL, 1.20 equiv.) and potassium carbonate (6.78 g, 49.1 mmol, 2.00 equiv.). The reaction was stirred at 80°C for 12 hours. The reaction mixture was quenched with water (50.0 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water (2 x 50.0 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 1-chloro-4-methoxy-2-methyl-5-nitrobenzene (4.90 g, 24.3 mmol, 99% yield) as a white oil.

Step 2: 5-Chloro-2-methoxy-4-methylaniline. To a solution of 1-chloro-4-methoxy-2-methyl-5-nitrobenzene (5.00 g, 24.8 mmol, 1.00 equiv.) in ethanol (30.0 mL) and water (10.0 mL), iron powder (4.15 g, 74.4 mmol, 3.00 equiv.) and ammonium chloride (6.63 g, 124 mmol, 5.00 equiv.) were added. The reaction was stirred at 80°C for 12 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was suspended in water (50.0 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water (2 x 50.0 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 5-chloro-2-methoxy-4-methylaniline (3.00 g, 17.5 mmol, 70% yield) as a yellow solid.

Step 3: 1-chloro-5-isocyanato-4-methoxy-2-methylbenzene. To a solution of 5-chloro-2-methoxy-4-methylaniline (1.00 g, 5.83 mmol, 1.00 equiv.) in toluene (10.0 mL) was added triphosgene (1.73 g, 5.83 mmol, 1.00 equiv.). The reaction was stirred at 100°C for 2 hours. The reaction mixture was concentrated in vacuo to afford 1-chloro-5-isocyanato-4-methoxy-2-methylbenzene (1.15 g, 5.82 mmol, 100% yield) as a yellow oil (solution in DCM (3 mL)), which was used directly in the next step.

Compound 77: The general procedure according to variant ii) was used for its preparation in 54% yield from compound VI using 1-isocyanato-4-(trifluoromethoxy)benzene. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (br s, 1H), 8.90 (s, 1H), 7.66 (s, 1H), 7.56 (d, J = 0.8 Hz, 2H), 7.53 - 7.48 (m, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.87 (br t, J = 5.6 Hz, 1H), 5.11 (dd, J = 5.2, 13.6 Hz, 1H), 4.47 - 4.38 (m, 3H), 4.34 - 4.27 (m, 1H), 2.99 - 2.85 (m, 1H), 2.64 - 2.55 (m, 1H), 2.43 - 2.35 (m, 1H), 2.04 - 1.96 (m, 1H).
MS (ESI) m/z 477.2 [M+H] ⁺

Compound 78: The general procedure according to variant ii) was used for its preparation in 32% yield from compound VI using 1,4-dichloro-2-isocyanato-5-methylbenzene. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 7.68 (s, 1H), 7.64 - 7.56 (m, 3H), 7.45 (s, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.52 - 4.39 (m, 3H), 4.38 - 4.26 (m, 1H), 3.00 - 2.81 (m, 1H), 2.64 - 2.58 (m, 1H), 2.39 (br dd, J = 7.9, 12.2 Hz, 1H), 2.25 (s, 3H), 2.05 - 1.95 (m, 1H).
MS (ESI) m/z 475.1 [M+H] ⁺
Scheme for the preparation of 1,4-dichloro-2-isocyanato-5-methylbenzene:

Step 1: To a solution of 2,5-dichloro-4-methylbenzoic acid (1.00 g, 4.88 mmol, 1.00 equiv.) and triethylamine (523 mg, 5.17 mmol, 720 uL, 1.06 equiv.) in toluene (50.0 mL) was added diphenyl azidophosphate (1.37 g, 4.97 mmol, 1.08 mL, 1.02 equiv.) at 20°C. The reaction mixture was stirred at 120°C for 2 hours. The reaction mixture was concentrated in vacuo. The residue was suspended in dichloromethane (4.00 mL) to give 1,4-dichloro-2-isocyanato-5-methylbenzene (985 mg, 4.88 mmol, 99.96% yield) as a yellow oil, which was used in the next step (in dichloromethane (4.00 mL)).

Compound 79: Prepared using General Procedure A with Variant iv) in 22% yield from Compound VI using 4-isocyanato-N,N-dimethylaniline.

¹ H NMR (400 MHz, DMSO-d ₆ + D ₂ O) δ = 7.72 - 7.46 (m, 7H), 5.06 (dd, J = 5.1, 13.3 Hz, 1H), 4.47 - 4.25 (m, 4H), 3.10 (s, 6H), 2.93 - 2.81 (m, 1H), 2.65 - 2.55 (m, 1H), 2.37 (dq, J = 4.3, 13.2 Hz, 1H), 2.05 - 1.93 (m, 1H). MS (ESI) m/z 436.2 [M+H] ⁺

Scheme for the preparation of 4-isocyanato-N,N-dimethylaniline.

Step 1: To a solution of 4-(dimethylamino)benzoic acid (1.00 g, 6.05 mmol, 1.00 equiv.) in toluene (50.0 mL), triethylamine (0.89 mL, 6.42 mmol, 1.06 equiv.) and diphenylphosphoryl azide (1.34 mL, 6.17 mmol, 1.02 equiv.) were added. The reaction was stirred at 20°C for 0.5 hours and then at 120°C for 2 hours. The mixture was concentrated under reduced pressure to give a residue. Dichloromethane (4.00 mL) was added to the residue to give 4-isocyanato-N,N-dimethylaniline (982 mg, crude) as a red oil.

Compound 80: Scheme for the preparation of compound 80.

Step 1: To a solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (500 mg, 2.11 mmol, 1.00 equiv.) in toluene (25.0 mL), triethylamine (0.31 mL, 2.23 mmol, 1.06 equiv.) and diphenyl azidophosphate (0.47 mL, 2.15 mmol, 1.02 equiv.) were added. The reaction was stirred at 20°C for 0.5 hours and then at 120°C for 2 hours. The mixture was concentrated under reduced pressure to give tert-butyl-(3-isocyanatophenyl)carbamate (490 mg, 2.09 mmol, 99% yield) as a yellow oil.

Step 2: To a solution of 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride VI (1.00 equiv., hydrochloride salt) in dimethylformamide (2.00 mL) was added triethylamine (0.11 mL, 0.77 mmol, 1.20 equiv.) and tert-butyl(3-isocyanatophenyl)carbamate (182 mg, 0.77 mmol, 1.20 equiv.) at 0°C. The reaction was stirred at 20°C for 1 hour. The mixture was concentrated under reduced pressure to give a residue, which was purified by reverse-phase column chromatography and lyophilized to give tert-butyl (3-(3-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)ureido)phenyl)carbamate (170 mg, 0.34 mmol, 52% yield) as a white solid.

Step 3: To a solution of tert-butyl (3-(3-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)ureido)phenyl)carbamate (150 mg, 0.30 mmol, 1.00 equivalents) in methanol (1.00 mL) was added 4N hydrochloric acid in methanol (1.00 mL). The reaction was stirred at 20°C for 0.5 hours. The mixture was concentrated under reduced pressure to give a residue that was purified by preparative HPLC and lyophilized to give compound 80 (77.8 mg, 0.17 mmol, 59% yield) as an off-white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.83 - 7.71 (m, 1H), 7.68 - 7.61 (m, 1H), 7.56 (d, J = 0.9 Hz, 2H), 7.39 - 7.29 (m, 1H), 7.28 - 7.19 (m, 1H), 7.00 - 6.76 (m, 1H), 5.07 (dd, J = 5.1, 13.3 Hz, 1H), 4.45 - 4.37 (m, 3H), 4.34 - 4.20 (m, 1H), 2.93 - 2.80 (m, 1H), 2.59 (td, J = 2.0, 15.3 Hz, 1H), 2.40 - 2.40 (m, 1H), 2.04 - 1.94 (m, 1H). MS (ESI) m/z 408.1 [M+H] ⁺

Compound 81: Scheme for the preparation of compound 81.

Step 1: To a solution of 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride VI (1.00 equiv., hydrochloride salt) in dimethylformamide (2.00 mL) was added triethylamine (0.09 ml, 645 μmol, 1.00 equiv.) and 1-isocyanato-4-nitrobenzene (106 mg, 0.65 mmol, 1.00 equiv.) at 0°C. The reaction was stirred at 20°C for 1 hour. The mixture was quenched with water (10.0 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]methyl]-3-(4-nitrophenyl)urea (200 mg, 0.56 mmol, 71% yield) as a black oil, which was used directly in the next step.

Step 2: To a solution of 1-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]methyl]-3-(4-nitrophenyl)urea (150 mg, 343 μmol, 1.00 equiv.) in methanol (3.00 mL), 10.0% wt. Pd/C on C (5 mg) and 4 M hydrochloric acid (8.57 μL, 0.10 equiv.) were added. The reaction was stirred under a hydrogen atmosphere (15 psi) at 20°C for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC and lyophilized to give compound 81 (20.0 mg, 43.8 μmol, 13% yield) as a black solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.0 (s, 1H), 10.52 - 9.67 (b, 3H), 9.24 (s, 1H), 7.66 (s, 1H), 7.57 (s, 2H), 7.53 (d, J = 8.9 Hz, 2H), 7.25 (d, J = 8.9 Hz, 2H), 7.08 (br s, 1H), 5.11 (dd, J = 5.0, 13.2 Hz, 1H), 4.48 - 4.27 (m, 4H), 2.98 - 2.81 (m, 1H), 2.60 (br d, J = 17.4Hz, 1H), 2.45 - 2.36 (m, 1H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 408.4 [M+H] ⁺

Compound 82: Scheme for the preparation of compound 82.

Step 1: To a solution of (3-chloro-2-methyl-5-nitrophenyl)methanol (2.00 g, 9.92 mmol, 1.00 equiv.) in dichloromethane (20.0 mL) was added thionyl chloride (3.60 mL, 49.6 mmol, 5.00 equiv.). The reaction was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to give 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene (2.20 g, 10.0 mmol, crude) as a yellow oil, which was used directly in the next step.

Step 2: To a solution of 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene (2.20 g, 10.0 mmol, 1.00 equivalents) and triethylamine (3.48 mL, 25.0 mmol, 2.50 equivalents) in acetonitrile (20.0 mL) was added morpholine (1.14 mL, 13.0 mmol, 1.30 equivalents). The reaction was stirred at 25°C for 10 hours. The mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to give 4-(3-chloro-2-methyl-5-nitrobenzyl)morpholine (0.510 g, 1.88 mmol, 19% yield) as a yellow solid.

Step 3: To a mixture of ethanol (8.00 mL) and water (4.00 mL) was added 4-(3-chloro-2-methyl-5-nitrobenzyl)morpholine (0.500 g, 1.85 mmol, 1.00 equiv.), ammonium chloride (98.8 mg, 1.85 mmol, 1.00 equiv.), and iron powder (516 mg, 9.23 mmol, 5.00 equiv.). The reaction was stirred at 90°C for 10 hours. The mixture was filtered and washed with ethyl acetate (20.0 mL). The filtrate was extracted with ethyl acetate (3 x 25.0 mL), and the combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3-chloro-4-methyl-5-(morpholinomethyl)aniline (0.45 g, 1.85 mmol, crude) as a yellow oil, which was used directly in the next step.

Step 4: To a solution of 3-chloro-4-methyl-5-(morpholinomethyl)aniline (0.100 g, 0.41 mol, 1.00 equiv.) in tetrahydrofuran (1.00 mL) was added 1,1'-carbonyldiimidazole (74.1 mg, 0.46 mmol, 1.10 equiv.). The mixture was stirred at 25°C for 2 hours, and then 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride VI (129 mg, 0.41 mmol, 1.00 equiv., hydrochloride salt) was added. The reaction was stirred at 25°C for 10 hours. The mixture was adjusted to pH 5 by adding HCl (1N) and then concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC to give compound 82 (16.26 mg, 29.8 μmol, 7% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.0 (s, 1H), 8.82 (s, 1H), 8.21 (s, 1H), 7.68 - 7.61 (m, 2H), 7.56 (d, J = 0.6 Hz, 2H), 7.12 (d, J = 2.0 Hz, 1H), 6.83 (br t, J = 5.6 Hz, 1H), 5.12 (dd, J = 5.0, 13.1 Hz, 1H), 4.46 - 4.27 (m, 4H), 3.54 (br s, 4H), 3.38 (br s, 2H), 2.97 - 2.85 (m, 1H), 2.63 - 2.59 (m, 1H), 2.42 - 2.38 (m, 1H), 2.35 (br s, 4H), 2.26 (s, 3H), 2.04 - 1.94 (m, 1H). MS (ESI) m/z 540.1 [M+H] ⁺

Compound 83: Prepared using General Procedure A with Variant iv) in 6% yield from Compound VI using 4-isocyanato-1-methyl-1H-pyrazole.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (br s, 1H), 8.85 (s, 1H), 7.64 (s, 1H), 7.58 - 7.52 (m, 2H), 7.47 (d, J = 2.4 Hz, 1H), 7.28 (br s, 1H), 6.05 (d, J = 2.0 Hz, 1H), 5.11 (dd, J = 4.8, 13.2 Hz, 1H), 4.49 - 4.26 (m, 4H), 3.68 (s, 3H), 2.98 - 2.85 (m, 1H), 2.64 - 2.55 (m, 1H), 2.46 - 2.36 (m, 1H), 2.06 - 1.94 (m, 1H). MS (ESI) m/z 397.1 [M+H] ⁺

Scheme for the preparation of 4-isocyanato-1-methyl-1H-pyrazole.

Step 1: To a mixture of 1-methyl-1H-pyrazole-4-carboxylic acid (400 mg, 3.17 mmol, 1.00 equiv.) and triethylamine (0.55 mL, 3.96 mmol, 1.25 equiv.) in toluene (5.00 mL) at 20°C, diphenylphosphoryl azide (0.83 mL, 3.81 mmol, 1.20 equiv.) was added in one portion. The mixture was stirred under nitrogen at 105°C for 3 hours. The mixture was cooled to 20°C and then concentrated under reduced pressure to afford 4-isocyanato-1-methyl-1H-pyrazole (1.80 g, crude) as a black oil, which was used directly in the next step.

Compound 84: Prepared using General Procedure A with Variant iv) in 37% yield from Compound VI using 3-isocyanatothiophene.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.04 (s, 1H), 8.99 (s, 1H), 7.71 (s, 1H), 7.61 (s, 2H), 7.42 (dd, J = 3.2, 5.2 Hz, 1H), 7.22 (dd, J = 1.2, 3.2 Hz, 1H), 7.04 (dd, J = 1.2, 5.2 Hz, 1H), 6.79 (t, J = 6.0 Hz, 1H), 5.17 (dd, J = 5.0, 13.2 Hz, 1H), 4.51 - 4.33 (m, 4H), 3.02 - 2.90 (m, 1H), 2.75 - 2.60 (m, 1H), 2.51 - 2.37 (m, 1H), 2.10 - 2.00 (m, 1H). MS (ESI) m/z 399.0 [M+H] ⁺

Scheme for the preparation of 3-isocyanatothiophene.

Step 1: To a suspension of thiophene-3-carboxylic acid (300 mg, 2.34 mmol, 1.00 equiv.) and triethylamine (407 μL, 2.93 mmol, 1.25 equiv.) in dry toluene (5.00 mL) under nitrogen at 25°C, diphenylphosphoryl azide (609 μL, 2.81 mmol, 1.20 equiv.) was added. The reaction was stirred at 25°C for 30 minutes and then heated to 100°C for 2 hours. The mixture was concentrated under reduced pressure to give 3-isocyanatothiophene (300 mg, crude) as a white solid, which was used directly in the next step.

Compound 85: Prepared using General Procedure A with Variant iv) in 59% yield from Compound VI using 1-chloro-5-isocyanato-2,4-dimethylbenzene.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (br s, 1H), 7.98 (s, 1H), 7.84 (br d, J = 3.1 Hz, 1H), 7.67 (s, 1H), 7.58 (d, J = 0.9 Hz, 2H), 7.25 - 7.15 (m, 1H), 7.09 (s, 1H), 5.12 (dd, J = 5.0, 13.3 Hz, 1H), 4.50 - 4.24 (m, 4H), 3.00 - 2.81 (m, 1H), 2.62 - 2.55 (m, 1H), 2.43 - 2.36 (m, 1H), 2.21 (s, 3H), 2.14 (s, 3H), 2.01 (ddd, J = 2.4, 5.3, 10.0 Hz, 1H). MS (ESI) m/z 455.2 [M+H] ⁺

Scheme for the preparation of 1-chloro-5-isocyanato-2,4-dimethylbenzene.

Step 1: To a solution of 2,4-dimethyl-5-nitroaniline (500 mg, 3.01 mmol, 1.00 equiv.) in concentrated hydrochloric acid (9.00 mL) was added a solution of sodium nitrite (208 mg, 3.01 mmol, 1.00 equiv.) in water (0.60 mL) at 0°C. The reaction was stirred at 0°C for 1 hour, and then cuprous chloride (477 mg, 4.81 mmol, 1.60 equiv.) was added at 0°C. The reaction was stirred at 20°C for 11 hours. Water (50.0 mL) was added, followed by potassium carbonate until pH = 7. The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 10/1) to obtain 1-chloro-2,4-dimethyl-5-nitrobenzene (400 mg, 2.16 mmol, 72% yield) as a yellow solid.

Step 2: To a solution of 1-chloro-2,4-dimethyl-5-nitrobenzene (350 mg, 1.89 mmol, 1.00 equiv.) in ethanol (12.0 mL) and water (3.00 mL), iron powder (315 mg, 5.66 mmol, 3 equiv.) and ammonium chloride (504 mg, 9.43 mmol, 5.00 equiv.) were added. The reaction was stirred at 80°C for 2 hours. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 10/1) to give 5-chloro-2,4-dimethylaniline (290 mg, 1.86 mmol, 99.0% yield) as a white solid.

Step 3: To a solution of 5-chloro-2,4-dimethylaniline (270 mg, 1.73 mmol, 1.00 equiv.) in toluene (10.0 mL), triphosgene (515 mg, 1.73 mmol, 1.00 equiv.) was added. The reaction was stirred at 100°C for 2 hours. The mixture was concentrated under reduced pressure to give 1-chloro-5-isocyanato-2,4-dimethylbenzene (315 mg, 1.73 mmol, 99.0% yield) as a yellow oil.

Compound 86: Prepared using General Procedure A with Variant iv) in 41% yield from Compound VI using 2-chloro-4-isocyanato-3-methoxy-1-methylbenzene.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.9 (br s, 1H), 8.24 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.57 (d, J = 0.7 Hz, 2H), 7.44 (br t, J = 5.8 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.37 (m, 3H), 4.36 - 4.25 (m, 1H), 3.74 (s, 3H), 2.96 - 2.83 (m, 1H), 2.65 - 2.55 (m, 1H), 2.42 - 2.34 (m, 1H), 2.25 (s, 3H), 2.05 - 1.91 (m, 1H). MS (ESI) m/z 471.2 [M+H] ⁺

Scheme for the preparation of 2-chloro-4-isocyanato-3-methoxy-1-methylbenzene.

Step 1: To a solution of 3-chloro-2-methoxy-4-methylbenzoic acid (300 mg, 1.50 mmol, 1.00 equiv.) in toluene (15.0 mL), triethylamine (0.22 mL, 1.59 mmol, 1.06 equiv.) and diphenyl azidophosphate (0.33 mL, 1.53 mmol, 1.02 equiv.) were added. The reaction was stirred at 20°C for 0.5 hours and then at 120°C for 2 hours. The mixture was concentrated under reduced pressure to give a residue. Dichloromethane (4.00 mL) was added to give 2-chloro-4-isocyanato-3-methoxy-1-methylbenzene (296 mg, crude) as a yellow oil.

Compound 87: Prepared using General Procedure A with Variant iv) in 41% yield from Compound VI using 2,3-dichloro-1-isocyanato-4-methylbenzene.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.9 (br s, 1H), 8.24 (s, 1H), 8.07 - 7.97 (m, 1H), 7.68 (s, 1H), 7.63 - 7.50 (m, 3H), 7.24 (d, J = 8.7 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.49 - 4.38 (m, 3H), 4.37 - 4.27 (m, 1H), 2.98 - 2.85 (m, 1H), 2.65 - 2.56 (m, 1H), 2.40 (br dd, J = 4.5, 13.1 Hz, 1H), 2.32 (s, 3H), 2.05 - 1.97 (m, 1H). MS (ESI) m/z 475.2 [M+H] ⁺

Scheme for the preparation of 2,3-dichloro-1-isocyanato-4-methylbenzene.

Step 1: To a solution of 3-chloro-4-methylaniline (5.00 g, 35.3 mmol, 1.00 equiv.) in N,N-dimethylformamide (50.0 mL) at 0°C, 1-chloropyrrolidine-2,5-dione (5.00 g, 37.4 mmol, 1.06 equiv.) in dimethylformamide (20.0 mL) was added dropwise. The reaction was stirred at 20°C for 12 hours. Water (50.0 mL) was added, and the mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (2 x 50.0 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 3/1) to give 2,3-dichloro-4-methylaniline (2.50 g, 14.2 mmol, 40.0% yield) as a black oil.

Compound 88: Prepared using General Procedure A with Variant iii) in 41% yield from Compound VI using phenyl(1-methyl-1H-pyrazol-3-yl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (br s, 1H), 8.85 (s, 1H), 7.64 (s, 1H), 7.58 - 7.52 (m, 2H), 7.47 (d, J = 2.4 Hz, 1H), 7.28 (br s, 1H), 6.05 (d, J = 2.0 Hz, 1H), 5.11 (dd, J = 4.8, 13.2 Hz, 1H), 4.49 - 4.26 (m, 4H), 3.68 (s, 3H), 2.98 - 2.85 (m, 1H), 2.64 - 2.55 (m, 1H), 2.46 - 2.36 (m, 1H), 2.06 - 1.94 (m, 1H). MS (ESI) m/z 397.1 [M+H] ⁺

Scheme for the preparation of phenyl(1-methyl-1H-pyrazol-3-yl)carbamate.

Step 1: To a solution of 1-methyl-1H-pyrazole-3-carboxylic acid (500 mg, 3.96 mmol, 1.00 equiv.) and triethylamine (0.55 mL, 3.96 mmol, 1.00 equiv.) in toluene (5.00 mL) was added diphenyl azidophosphate (0.86 mL, 3.96 mmol, 1.00 equiv.) at 25°C. The reaction was stirred at 25°C for 30 minutes. The mixture was concentrated under reduced pressure to give 1-methyl-1H-pyrazole-3-carbonyl azide (600 mg, crude) as a black solid, which was used directly in the next step.

Step 2: To a solution of phenol (2.96 mL, 33.7 mmol, 11.3 equiv.) in toluene (22.0 mL) was added 1-methyl-1H-pyrazole-3-carbonyl azide (450 mg, 2.98 mmol, 1.00 equiv.) at 100°C. The reaction was stirred at 100°C for 3 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 0/1 to 3/1) to give phenyl (1-methyl-1H-pyrazol-3-yl)carbamate (160 mg, 0.66 mmol, 22% yield) as a red solid.

Compound 89: Prepared using General Procedure A with Variant iv) in 7% yield from Compound VI using 3-isocyanato-N,N-dimethylaniline.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.00 (br s, 1H), 8.52 (s, 1H), 8.32 (s, 1H), 7.66 (s, 1H), 7.56 (d, J = 0.9 Hz, 2H), 7.04 - 6.97 (m, 1H), 6.88 (t, J = 2.1 Hz, 1H), 6.79 - 6.65 (m, 2H), 6.30 (dd, J = 2.1, 8.2 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.46 - 4.26 (m, 4H), 3.02 - 2.89 (m, 1H), 2.85 (s, 6H), 2.60 (td, J = 1.9, 15.4 Hz, 1H), 2.39 (br dd, J = 4.5, 13.0 Hz, 1H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 436.2 [M+H] ⁺

Scheme for the preparation of 3-isocyanato-N,N-dimethylaniline.

Step 1: To a solution of 3-(dimethylamino)benzoic acid (1.00 g, 6.05 mmol, 1.00 equiv.) in toluene (50.0 mL), triethylamine (0.89 mL, 6.42 mmol, 1.06 equiv.) and diphenylphosphoryl azide (1.34 mL, 6.17 mmol, 1.02 equiv.) were added. The reaction was stirred at 20°C for 0.5 hours and then at 120°C for 2 hours. The mixture was concentrated under reduced pressure to give a residue. Dichloromethane (4.00 mL) was added to the residue to give 4-isocyanato-N,N-dimethylaniline (982 mg, crude) as a red oil.

Compound 90: Prepared using General Procedure A with Variant iv) in 35% yield from Compound VI using 1-isocyanato-3-(trifluoromethoxy)benzene.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ =10.98 (br s, 1H), 9.02 (s, 1H), 7.67 (s, 2H), 7.57 (d, J = 0.7 Hz, 2H), 7.37 - 7.30 (m, 1H), 7.29 - 7.22 (m, 1H), 6.91 (br t, J = 5.9 Hz, 1H), 6.88 - 6.83 (m, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.49 - 4.36 (m, 3H), 4.36 - 4.26 (m, 1H), 2.98 - 2.85 (m, 1H), 2.60 (td, J = 2.0, 15.4 Hz, 1H), 2.40 (br dd, J = 4.5, 13.0 Hz, 1H), 2.05 - 1.96 (m, 1H). MS (ESI) m/z 477.2 [M+H] ⁺

Compound 91: Prepared using General Procedure A with Variant iv) in 11% yield from Compound VI using 2-isocyanatothiophene.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.96 (br s, 1H), 9.64 (s, 1H), 7.65 (s, 1H), 7.56 (s, 2H), 6.86 (br t, J = 6.0 Hz, 1H), 6.79 - 6.72 (m, 2H), 6.44 (dd, J = 1.6, 3.2 Hz, 1H), 5.11 (dd, J = 5.2, 13.2 Hz, 1H), 4.49 - 4.24 (m, 4H), 2.97 - 2.84 (m, 1H), 2.64 - 2.55 (m, 1H), 2.44 - 2.36 (m, 1H), 2.04 - 1.95 (m, 1H). MS (ESI) m/z 399.0 [M+H] ⁺
Scheme for the preparation of 2-isocyanatothiophene:

Step 1: To a solution of thiophene-2-carboxylic acid (300 mg, 2.34 mmol, 1.00 equiv.) and triethylamine (0.33 mL, 2.34 mmol, 1.00 equiv.) in toluene (1.50 mL) was added diphenyl azidophosphate (0.51 mL, 2.34 mmol, 1.00 equiv.) at 25°C. The reaction was stirred at 25°C for 30 minutes. Water (1.00 mL) was added, and the mixture was extracted with ethyl acetate (3 x 5.00 mL). The organic layers were combined, washed with saturated sodium bicarbonate (1.00 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give thiophene-2-carbonyl azide (350 mg, crude) as an off-white solid.

Step 2: Thiophene-2-carbonyl azide (400 mg, 2.61 mmol, 1.00 equiv.) in toluene (4.00 mL) was stirred at 120°C for 30 minutes to give 2-isocyanatothiophene, which was used directly in the next step.

Compound 92: Prepared using General Procedure A with Variant iii) in 12% yield from Compound VI using phenylthiazol-2-ylcarbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.0 (br s, 1H), 10.8 - 10.5 (m, 1H), 8.38 (s, 1H), 7.65 (s, 1H), 7.57 (d, J = 0.6 Hz, 2H), 7.31 (d, J = 3.6 Hz, 1H), 7.27 (br s, 1H), 7.02 (d, J = 3.6 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.51 - 4.37 (m, 3H), 4.34 - 4.25 (m, 1H), 3.02 - 2.84 (m, 1H), 2.69 - 2.55 (m, 1H), 2.46 - 2.28 (m, 1H), 2.06 - 1.91 (m, 1H). MS (ESI) m/z 400.2 [M+H] ⁺

Scheme for the preparation of phenylthiazol-2-ylcarbamates.

Step 1: To a solution of thiazol-2-amine (1.00 g, 9.99 mmol, 1.00 equiv.) in dichloromethane (5.00 mL), pyridine (4.84 mL, 60.0 mmol, 6.00 equiv.) and phenyl chloroformate (1.50 mL, 12.0 mmol, 1.20 equiv.) were added. The reaction was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 1/1) to give phenyl thiazol-2-ylcarbamate (1.00 g, 4.54 mmol, 45% yield) as a white solid.

Compound 93: Prepared using General Procedure A with Variant iv) in 34% yield from Compound VI using 2-chloro-4-isocyanato-1,3-dimethylbenzene.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.0 (s, 1H), 7.97 (s, 1H), 7.67 (s, 1H), 7.57 (d, J = 0.7 Hz, 2H), 7.54 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 7.03 (br t, J = 5.9 Hz, 1H), 5.12 (dd, J = 5.0, 13.3 Hz, 1H), 4.50 - 4.36 (m, 3H), 4.35 - 4.26 (m, 1H), 2.98 - 2.83 (m, 1H), 2.60 (br d, J = 18.0 Hz, 1H), 2.40 (br dd, J = 4.4, 13.1 Hz, 1H), 2.27 (s, 3H), 2.24 (s, 3H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 455.2 [M+H] ⁺

Scheme for the preparation of 2-chloro-4-isocyanato-1,3-dimethylbenzene:

Step 1: To a solution of 2-chloro-1,3-dimethylbenzene (4.43 mL, 33.4 mmol, 1.00 equiv.) in sulfuric acid (20.0 mL) was added nitric acid (1.50 mL, 33.4 mmol, 1.00 equiv.) dropwise at 0°C. The reaction was stirred at 20°C for 2 hours. The mixture was poured into ice water (20.0 mL) and extracted with ethyl acetate (2 x 20.0 mL). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0) to give 2-chloro-1,3-dimethyl-4-nitrobenzene (2.10 g, 11.3 mmol, 34.0% yield) as a white solid.

Step 2: To a solution of 2-chloro-1,3-dimethyl-4-nitrobenzene (2.10 g, 11.3 mmol, 1.00 equiv.) in ethanol (24.0 mL) and water (8.00 mL), ammonium chloride (6.05 g, 113 mmol, 10.0 equiv.) and Fe (3.79 g, 67.9 mmol, 6.00 equiv.) were added. The reaction was stirred at 80°C for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 3/1) to give 3-chloro-2,4-dimethylaniline (1.25 g, 8.03 mmol, 71.0% yield) as a pale yellow oil.

Step 3: To a solution of 3-chloro-2,4-dimethylaniline (300 mg, 1.93 mmol, 1.00 equiv.) in toluene (12.0 mL) was added bis(trichloromethyl)carbonate (572 mg, 1.93 mmol, 1.00 equiv.). The reaction was stirred at 100°C for 3 hours. The mixture was concentrated under reduced pressure to give a residue. Dichloromethane (1.00 mL) was added to the residue to give 2-chloro-4-isocyanato-1,3-dimethylbenzene (350 mg, crude) as a yellow oil.

Compound 94: Prepared using General Procedure A with Variant iii) in 16% yield from Compound VI using phenylisoxazol-3-ylcarbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.0 (s, 1H), 9.63 (s, 1H), 8.67 (d, J = 1.6 Hz, 1H), 7.65 (s, 1H), 7.59−7.51 (m, 2H), 7.12 (t, J = 6.0 Hz, 1H), 6.72 (d, J = 1.6 Hz, 1H), 5.12 (dd, J = 4.2, 13.2 Hz, 1H), 4.51-4.24 (m, 4H), 3.00-2.80 (m, 1H), 2.71-2.58 (m, 1H), 2.39-2.25 (m, 1H), 2.06-1.91 (m, 1H). LCMS m/z=384.0[M+H] ⁺

Scheme for the preparation of phenylisoxazol-3-ylcarbamates.

Step 1: To a solution of isoxazol-3-amine (500 mg, 5.95 mmol, 1.00 equiv.) in tetrahydrofuran (20.0 mL) at 20°C, phenyl chloroformate (1.02 g, 6.54 mmol, 1.10 equiv.) and triethylamine (1.20 g, 11.9 mmol, 2.00 equiv.) were added dropwise. The reaction was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column chromatography to give phenyl isoxazol-3-ylcarbamate (130 mg, 598 μmol, 10% yield) as a yellow solid.

Compound 95: Scheme for the preparation of compound 95.

Step 1: To a mixture of nicotinic acid (500 mg, 4.06 mmol, 1.00 equiv.) and triethylamine (534 mg, 5.28 mmol, 1.30 equiv.) in toluene (5 mL) at 20°C, diphenylphosphoryl azide (1.68 g, 6.09 mmol, 1.50 equiv.) was added dropwise. The reaction was stirred at 20°C for 1 hour. Triethylamine (1.64 g, 16.3 mmol, 4.00 equiv.) and 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride VI (555 mg, 1.79 mmol, 0.44 equiv., hydrochloride salt) were added in one portion. The reaction was stirred at 100°C for 2 hours. The mixture was diluted with ethyl acetate (50 mL) and poured into saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (10 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/0 to 85/15), preparative TLC (dichloromethane/methanol = 10/1), and reverse-phase preparative HPLC to give compound 95 (19.3 mg, 48.9 μmol, 3% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.0 (s, 1H), 8.94 (s, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.15−8.08 (m, 1H), 7.94−7.86 (m, 1H), 7.68 (s, 1H), 7.57 (s, 2H), 7.29-7.20 (m, 1H), 7.02 (m, 1H), 5.17-5.06 (m, 1H), 4.48-4.28 (m, 4H), 2.94-2.86 (m, 1H), 2.65-2.58 (m, 1H), 2.46－2.37 (m, 1H), 2.05-1.96 (m, 1H). LCMS m/z 394.1 [M+H] ⁺

Compound 96: It was prepared using General Procedure A with Variant iv) in 56% yield from Compound VI using 1,4-dichloro-2-isocyanato-3,5-dimethylbenzene.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ =11.0 (br s, 1H), 8.06 (s, 1H), 7.69 (s, 1H), 7.55 (s, 2H), 7.40 (s, 1H), 6.94 (br s, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.49 - 4.27 (m, 4H), 2.97 - 2.83 (m, 1H), 2.60 (td, J = 2.0, 15.3 Hz, 1H), 2.40 (br dd, J = 4.5, 13.0 Hz, 1H), 2.32 (s, 3H), 2.28 - 2.21 (m, 3H), 2.04 - 1.96 (m, 1H). MS (ESI) m/z 489.2 [M+H] ⁺

Scheme for the preparation of 1,4-dichloro-2-isocyanato-3,5-dimethylbenzene.

Step 1: To a solution of 3-chloro-2,4-dimethylaniline (780 mg, 5.01 mmol, 1.00 equiv.) in dimethylformamide (10.5 mL) was added a solution of 1-chloropyrrolidine-2,5-dione (709 mg, 5.31 mmol, 1.06 equiv.) in dimethylformamide (7.00 mL). The reaction was stirred at 20°C for 12 hours and then concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give 3,6-dichloro-2,4-dimethylaniline (290 mg, 1.53 mmol, 30% yield) as a red oil.

Step 2: To a solution of 3,6-dichloro-2,4-dimethylaniline (290 mg, 1.53 mmol, 1.00 equiv.) in toluene (12.0 mL) was added bis(trichloromethyl)carbonate (453 mg, 1.53 mmol, 1.00 equiv.). The reaction was stirred at 100°C for 3 hours. The mixture was concentrated under reduced pressure to give a residue. Dichloromethane (1.00 mL) was added to the residue to give 1,4-dichloro-2-isocyanato-3,5-dimethylbenzene (329 mg, crude) as a red oil.

Compound 97: Scheme for the preparation of compound 97.

Step 1: To a mixture of 5-methylisoxazole-3-carboxylic acid (700 mg, 5.51 mmol, 1.00 equiv.) and triethylamine (725 mg, 7.16 mmol, 1.30 equiv.) in toluene (5 mL) at 20°C, diphenylphosphoryl azide (2.58 g, 9.36 mmol, 1.70 equiv.) was added dropwise. The mixture was stirred at 20°C for 1 hour. Triethylamine (836 mg, 8.26 mmol, 1.5 equiv.) and 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride VI (500 mg, 1.61 mmol, 0.293 equiv., hydrochloride salt) were added, and the reaction was stirred at 100°C for 2 hours. The mixture was cooled to 20°C and diluted with ethyl acetate (50.0 mL). The mixture was poured into saturated aqueous sodium bicarbonate (100 mL), the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (5 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/0 to 90/10), preparative TLC (dichloromethane/methanol = 10/1), and reverse-phase preparative HPLC to give compound 97 (51.5 mg, 129 μmol, 2% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.9 (br s, 1H), 9.57−9.43 (m, 1H), 7.64 (s, 1H), 7.56 (s, 2H), 7.13 (br s, 1H), 6.40 (s, 1H), 5.19-5.04 (m, 1H), 4.49-4.37 (m, 3H), 4.35-4.24 (m, 1H), 2.98-2.83 (m, 1H), 2.64-2.55 (m, 1H), 2.43-2.36 (m, 1H), 2.32 (s, 3H), 2.05-1.93 (m, 1H).LCMS m/z 398.1 [M+H] ⁺

Compound 98: Prepared using General Procedure A with Variant iii) in 20% yield from Compound VI using phenyl 1H-pyrrol-3-ylcarbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.0 (br s, 1H), 10.3 (br s, 1H), 7.98 (s, 1H), 7.63 (s, 1H), 7.56 - 7.51 (m, 2H), 6.73 (s, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.43 (t, J = 6.0 Hz, 1H), 5.85 (d, J = 1.6 Hz, 1H), 5.11 (dd, J = 7.6, 13.2 Hz, 1H), 4.49 - 4.23 (m, 4H), 2.97 - 2.84 (m, 1H), 2.64 - 2.55 (m, 1H), 2.47 - 2.35 (m, 1H), 2.03 - 1.95 (m, 1H). MS (ESI) m/z 382.1 [M+H] ⁺

Scheme for the preparation of phenyl 1H-pyrrol-3-ylcarbamate.

Step 1: To a solution of 1H-pyrrole-3-carboxylic acid (500 mg, 4.50 mmol, 1.00 equiv.) and triethylamine (0.63 mL, 4.50 mmol, 1.00 equiv.) in toluene (1.00 mL) was added diphenyl azidophosphate (0.97 mL, 4.50 mmol, 1.00 equiv.) at 25°C. The reaction was stirred at 25°C for 1 hour. This mixture was used directly in the next step.

Step 2: To a solution of phenol (4.39 mL, 49.9 mmol, 11.3 equivalents) in toluene (15.0 mL) was added 1H-pyrrole-3-carbonyl azide (600 mg, 4.41 mmol, 1.00 equivalents) at 100°C. The mixture was stirred at 100°C for 1 hour. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 0/1 to 4/1) to give phenyl 1H-pyrrol-3-ylcarbamate (0.50 g, 2.32 mmol, 53% yield) as a red solid.

Compound 99: Prepared using General Procedure A with Variant iii) in 20% yield from Compound VI using phenylthiazol-4-ylcarbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.0 (s, 1H), 9.46 (s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 7.66 (s, 1H), 7.57 (s, 2H), 7.21 (d, J = 2.4 Hz, 1H), 6.94 (br t, J = 5.6 Hz, 1H), 5.12 (dd, J = 5.2, 13.2 Hz, 1H), 4.49 - 4.26 (m, 4H), 2.98 - 2.85 (m, 1H), 2.65 - 2.56 (m, 1H), 2.45 - 2.37 (m, 1H), 2.06 - 1.94 (m, 1H). MS (ESI) m/z 400.2 [M+H] ⁺

Scheme for the preparation of phenylthiazol-4-ylcarbamates.

Step 1: To a solution of thiazole-4-carboxylic acid (0.50 g, 3.87 mmol, 1.00 equiv.) and triethylamine (0.54 mL, 3.87 mmol, 1.00 equiv.) in toluene (4.00 mL) was added diphenyl azidophosphate (0.84 mL, 1.07 g, 3.87 mmol, 1.00 equiv.) at 25°C. The mixture was stirred at 25°C for 30 minutes. This mixture was used directly in the next step.

Step 2: To a solution of phenol (4.39 mL, 49.9 mmol, 11.3 equiv.) in toluene (15.0 mL) was added thiazole-4-carbonyl azide (0.60 g, 4.41 mmol, 1.00 equiv.) at 100°C. The reaction was stirred at 100°C for 1 hour. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 0/1 to 5/1) to give phenylthiazol-4-ylcarbamate (200 mg, 0.91 mmol, 23% yield) as a white solid.

Compound 100: Prepared using General Procedure A with Variant iv) in 20% yield from Compound VI using 2,3-dichloro-4-isocyanato-1,5-dimethylbenzene.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.0 (s, 1H), 8.01 (s, 1H), 7.69 (s, 1H), 7.55 (s, 2H), 7.22 (s, 1H), 6.91 (br t, J = 5.4 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.52 - 4.24 (m, 4H), 2.91 (ddd, J = 5.4, 13.7, 17.3 Hz, 1H), 2.63 - 2.57 (m, 1H), 2.44 - 2.38 (m, 1H), 2.34 (s, 3H), 2.17 (s, 3H), 2.05 - 1.93 (m, 1H). MS (ESI) m/z 489.2 [M+H] ⁺

Scheme for the preparation of 2,3-dichloro-4-isocyanato-1,5-dimethylbenzene.

Step 1: To a solution of 5-chloro-2,4-dimethylaniline (1.50 g, 9.64 mmol, 1.00 equiv.) in dimethylformamide (15.00 mL) was added a solution of 1-chloropyrrolidine-2,5-dione (1.36 g, 10.2 mmol, 1.06 equiv.) in dimethylformamide (6.00 mL). The reaction was stirred at 20°C for 12 hours. Water (20.0 mL) was added to the mixture, which was then extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with brine (2 x 50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 10/1) to give 2,3-dichloro-4,6-dimethylaniline (1.00 g, 5.26 mmol, 55% yield) as a yellow oil.

Step 2: To a solution of 2,3-dichloro-4,6-dimethylaniline (500 mg, 2.63 mmol, 1.00 equiv) in toluene (10.0 mL) was added triphosgene (781 mg, 2.63 mmol, 1.00 equiv). The reaction was stirred at 100° C. for 2 hours. The mixture was concentrated under reduced pressure to give 2,3-dichloro-4-isocyanato-1,5-dimethylbenzene (560 mg, 2.59 mmol, 99% yield) as a yellow oil.
Compound 101: Scheme for the preparation of compound 101:

Step 1: To a mixture of 2-methyl-5-nitrobenzoic acid (5.00 g, 27.6 mmol, 1.00 equiv.) in tetrahydrofuran (138 mL) at 20°C, borane dimethyl sulfide complex (10.0 M, 5.52 mL, 2.00 equiv.) was added dropwise. The reaction was stirred at 75°C under a nitrogen atmosphere for 4 hours. The mixture was cooled to 5°C, and methanol/water (25.0 mL, v/v = 1:1) was added, followed by 5N hydrochloric acid (50.0 mL). The mixture was concentrated under reduced pressure to give a slurry, which was poured into water (50.0 mL) and extracted with ethyl acetate (4 x 50.0 mL). The combined organic layers were washed with brine (50.0 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 100/1 to 80/20) to obtain (2-methyl-5-nitrophenyl)methanol (4.75 g, 27.6 mmol, 100% yield) as a white solid.

Step 2: To a mixture of (2-methyl-5-nitrophenyl)methanol (1.00 g, 5.98 mmol, 1.00 equiv.) in dichloromethane (10.0 mL) at 20°C, thionyl chloride (4.34 mL, 59.8 mmol, 10.0 equiv.) and N-methylpyrrolidone (0.58 mL, 5.98 mmol, 1.00 equiv.) were added dropwise. The reaction was stirred at 25°C for 4 hours. The reaction was carefully quenched with water (50.0 mL) and extracted with ethyl acetate (4 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 70/30 to 60/40) to obtain 2-(chloromethyl)-1-methyl-4-nitrobenzene (1.10 g, 5.93 mmol, 99% yield) as a white solid.

Step 3: To a mixture of 2-(chloromethyl)-1-methyl-4-nitrobenzene (500 mg, 2.69 mmol, 1.00 equiv.) in dimethylformamide (1.50 mL) and acetonitrile (1.50 mL) at 20°C, N,N-diisopropylethylamine (1.04 g, 8.08 mmol, 3.00 equiv.) and morpholine (258 mg, 2.96 mmol, 1.10 equiv.) were added dropwise. The reaction was stirred at 60°C for 10 hours. The mixture was cooled to 20°C and concentrated under reduced pressure to give a slurry, which was poured into water (50.0 mL), and the mixture was extracted with ethyl acetate (4 x 50.0 mL). The combined organic layers were washed with brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/90 to 0/100) to obtain 4-(2-methyl-5-nitrobenzyl)morpholine (584 mg, 2.47 mmol, 91% yield) as a pale yellow solid.

Step 4: To a mixture of 4-(2-methyl-5-nitrobenzyl)morpholine (584 mg, 2.47 mmol, 1.00 equiv.) in ethanol (5.00 mL) and water (5.00 mL), ammonium chloride (132 mg, 2.47 mmol, 1.00 equiv.) and iron powder (690 mg, 12.4 mmol, 5.00 equiv.) were added. The reaction was stirred at 90°C for 10 hours. The mixture was cooled to 20°C and filtered. The filter cake was washed with methanol (2 x 20.0 mL). The filtrate was concentrated under reduced pressure to give a slurry. The slurry was poured into saturated aqueous sodium bicarbonate (50.0 mL) and extracted with ethyl acetate (4 x 50.0 mL). The combined organic layers were washed with brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/90 to 0/100) to obtain 4-methyl-3-(morpholinomethyl)aniline (482 mg, 2.34 mmol, 95% yield) as a pale yellow solid.

Step 5: To a mixture of 4-methyl-3-(morpholinomethyl)aniline (200 mg, 0.969 mmol, 1.50 equiv.) and triethylamine (98.0 mg, 0.969 mmol, 1.50 equiv.) in tetrahydrofuran (10.0 mL), 1,1'-carbonyldiimidazole (157 mg, 0.969 mmol, 1.50 equiv.) was added. The reaction was stirred at 20°C for 1 hour. A mixture of 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride IV (200 mg, 0.646 mmol, 1.00 equiv., hydrochloride salt) and triethylamine (196 mg, 1.94 mmol, 3.00 equiv.) in tetrahydrofuran (2.00 mL) was added. The reaction was stirred at 25°C for 14 hours. The mixture was quenched with water (50.0 ml) and extracted with ethyl acetate (4 x 50.0 mL). The combined organic layers were washed with brine (20.0 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC to give 1-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)-3-(4-methyl-3-(morpholinomethyl)phenyl)urea (68.4 mg, 0.135 mmol, 20% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (br s, 1H), 8.56 (s, 1H), 7.66 (s, 1H), 7.56 (d, J = 0.8 Hz, 2H), 7.31−7.20 (m, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.71 (t, J = 6.0 Hz, 1H), 5.11 (dd, J = 4.8, 13.2 Hz, 1H), 4.38 (d, J = 5.6 Hz, 2H), 4.37 (dd, J = 17.2, 51.6 Hz, 2H), 3.55 (t, J = 4.4 Hz, 4H), 3.34 (s, 2H), 2.91 (dddd, J = 5.6, 9.6, 17.6, 31.2 Hz, 1H), 2.64-2.56 (m, 1H), 2.45 - 2.38 (m, 1H), 2.37-2.30 (m, 4H), 2.22 (s, 3H), 2.04-1.95 (m, 1H). LCMS m/z 506.5 [M+H] ⁺

Compound 102: Scheme for the preparation of compound 102.

Step 1: To a solution of 3-nitro-1H-pyrazole (5.00 g, 44.2 mmol, 1.00 equiv.) in tetrahydrofuran (100 mL) was added 60% pure sodium hydride (2.13 g, 53.3 mmol, 1.20 equiv.) at 0°C. The reaction was stirred for 10 minutes, and 2-(trimethylsilyl)ethoxymethyl chloride (8.60 mL, 48.6 mmol, 1.10 equiv.) was added dropwise. The reaction was stirred at 20°C for 1 hour. The mixture was quenched with ice water (150 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain trimethyl-[2-[(3-nitropyrazol-1-yl)methoxy]ethyl]silane (6.20 g, 25.4 mmol, 57% yield) as a clear oil.

Step 2: To a solution of trimethyl-[2-[(3-nitropyrazol-1-yl)methoxy]ethyl]silane (3.00 g, 12.3 mmol, 1.00 equiv.) in methanol (50.0 mL) was added 10% by weight of Pd/C on C (0.50 g). The reaction was stirred under a hydrogen atmosphere (15 psi) at 30°C for 4 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 1-(2-trimethylsilylethoxymethyl)pyrazol-3-amine (2.40 g, 11.2 mmol, 91% yield) as a white solid.

Step 3: To a solution of 1-(2-trimethylsilylethoxymethyl)pyrazol-3-amine (1.00 g, 4.69 mmol, 1.00 equiv.) and pyridine (0.76 mL, 9.37 mmol, 2.00 equiv.) in acetonitrile (8.00 mL) at 0°C was added phenyl chloroformate (0.70 mL, 5.62 mmol, 1.20 equiv.) in acetonitrile (2.00 mL). The reaction was stirred at 25°C for 3 hours. The mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (2 x 20.0 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 6/1) and concentrated under reduced pressure to give phenyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)carbamate (1.40 g, 4.20 mmol, 89% yield) as a yellow solid.

Step 4: To a solution of 3-[6-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride VI (200 mg, 645 μmol, 1.00 equiv., hydrochloride salt) and triethylamine (196 mg, 1.94 mmol, 267 μL, 3.00 equiv.) in dimethylformamide (3.00 mL) was added phenyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)carbamate (258 mg, 775 μmol, 1.20 equiv.). The reaction was stirred at 25°C for 12 hours. The mixture was diluted with water (20.0 mL) and extracted with dichloromethane/isopropyl alcohol = 3/1 (3 x 15.0 mL). The combined organic layers were washed with brine (2 x 20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)urea (360 mg, crude) as a yellow solid, which was used directly in the next reaction.

Step 5: A mixture of 1-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)urea (360 mg, 702 μmol, 1.00 equiv.) in trifluoroacetic acid (1.00 mL) and dichloromethane (1.00 mL) was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC and lyophilized to give compound 102 (88 mg, 205 μmol, 29% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.12 (br s, 1H), 10.99 (br s, 1H), 8.91 (s, 1H), 8.30 (br s, 1H), 7.64 (s, 1H), 7.56 (s, 2H), 7.53 (d, J = 2.0 Hz, 1H), 7.44 (br s, 1H), 6.06 (s, 1H), 5.11 (dd, J = 5.2, 13.2 Hz, 1H), 4.46 - 4.40 (m, 3H), 4.33 - 4.27 (m, 1H), 2.97 - 2.85 (m, 1H), 2.64 - 2.55 (m, 1H), 2.45 - 2.32 (m, 1H), 2.05 - 1.94 (m, 1H). MS (ESI) m/z 383.3 [M+H] ⁺

Compound 103: Prepared using General Procedure A with Variant iii) in 61% yield from Compound VI using phenyl N-thiazol-5-ylcarbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 1.96 - 2.03 (m, 1 H) 2.39 (br dd, J = 13.39, 4.71 Hz, 1 H) 2.55 - 2.64 (m, 1 H) 2.83 - 2.97 (m, 1 H) 4.26 - 4.48 (m, 4 H) 5.11 (dd, J = 13.2, 5.2 Hz, 1 H) 7.09 - 7.16 (m, 1 H) 7.39 (d, J = 0.8 Hz, 1 H) 7.56 (s, 2 H) 7.65 (s, 1 H) 8.40 (s, 1 H) 9.92 (br s, 1H) 10.91 - 11.05 (m, 1 H). LCMS m/z 400.0 [M+H] ⁺

Scheme for the preparation of phenyl N-thiazol-5-ylcarbamate.

Step 1: To a vigorously stirred suspension of ethyl thiazole-5-carboxylate (1.84 g, 11.7 mmol, 1.00 equiv.) in methanol (11.0 mL), sodium hydroxide (1.40 g, 35.1 mmol, 3.00 equiv.) was added. The reaction was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure, and the residual aqueous suspension was acidified to pH 1-2 with 6 M aqueous hydrogen chloride. The solid was filtered to afford thiazole-5-carboxylic acid (1.31 g, 10.2 mmol, 86% yield) as a white solid.

Step 2: To a solution of thiazole-5-carboxylic acid (1.31 g, 10.2 mmol, 1.00 equiv.) in 1,4-dioxane (33.0 mL), triethylamine (1.61 mL, 11.59 mmol, 1.14 equiv.) and diphenylphosphoryl azide (2.51 mL, 11.6 mmol, 1.14 equiv.) were added. The reaction was stirred at 20°C for 3 hours. Phenol (10.2 mL, 116.21 mmol, 11.43 equiv.) was added dropwise, and the reaction was stirred at 100°C for 3 hours. The mixture was cooled to 20°C and then concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 1/1) to give phenyl N-thiazol-5-ylcarbamate (813 mg, 3.69 mmol, 36% yield) as a brown solid.

Compound 104: Prepared using General Procedure A with Variant iii) in 61% yield from Compound VI using phenylpyridin-4-ylcarbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 9.14 (s, 1H), 8.29 (d, J = 6.4 Hz, 2H), 8.14 (s, 1H), 7.67 (s, 1H), 7.57 (d, J = 0.8 Hz, 2H), 7.43−7.37 (m, 2H), 7.02 (t, J = 6.0 Hz, 1H), 5.11 (dd, J = 4.8, 13.2 Hz, 1H), 4.415 (d, J = 5.6 Hz, 2H), 4.37 (dd, J = 17.2, 52.4 Hz, 2H), 2.96-2.84 (m, 1H), 2.65-2.56 (m, 1H), 2.43-2.34 (m, 1H), 2.05-1.95 (m, 1H). LCMS m/z 394.1 [M+H] ⁺

Scheme for the preparation of phenylpyridin-4-ylcarbamates.

A mixture of pyridin-4-amine (3.57 mL, 21.3 mmol, 1.00 equiv.), phenyl chloroformate (2.93 mL, 23.4 mmol, 1.10 equiv.), and triethylamine (5.92 mL, 42.5 mmol, 2.00 equiv.) in tetrahydrofuran (30.0 mL) was stirred at 20°C for 0.5 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column chromatography and lyophilized to give phenylpyridin-4-ylcarbamate (1.13 g, 5.26 mmol, 56% yield) as a white solid.

Compound 105: Scheme for the preparation of compound 105.

Step 1: To a solution of 3-(morpholinomethyl)aniline (279 mg, 1.45 mmol, 1.50 equiv.) and triethylamine (196 mg, 1.94 mmol, 2.00 equiv.) in dimethylformamide (5.00 mL) was added di(1H-imidazol-1-yl)methanone (236 mg, 1.45 mmol, 1.50 equiv.). The reaction was stirred at 20°C for 2 hours, followed by the addition of a solution of 3-(6-(aminomethyl)-1-oxo-isoindolin-2-yl)piperidine-2,6-dione hydrochloride VI (300 mg, 969 μmol, 1.00 equiv., hydrochloride salt) and triethylamine (294 mg, 2.91 mmol, 3.00 equiv.) in dimethylformamide (5.00 mL). The reaction was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate/methanol = 100/0 to 80/20) and then reverse-phase preparative HPLC, and then lyophilized to give compound 105 (29.6 mg, 53.5 μmol, 5% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.69 (s, 1H), 8.19 (s, 1H), 7.66 (s, 1H), 7.56 (d, J = 0.8 Hz, 2H), 7.37 (s, 1H), 7.33-7.28 (m, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.77 (t, J = 6.0 Hz, 1H), 5.11 (dd, J = 5.2, 13.2 Hz, 1H), 4.39 (d, J = 5.6 Hz, 2H), 4.37 (dd, J = 16.8, 52.0 Hz, 2H), 3.58-3.54 (m, 4H), 3.38 (s, 2H), 2.91 (ddd, J = 5.2, 13.6, 17.2 Hz, 1H), 2.65-2.55 (m, 1H), 2.43-2.36 (m, 1H), 2.36-2.30 (m, 4H), 2.04-1.96 (m, 1H). LCMS m/z 492.2 [M+H] ⁺

Compound 106: Scheme for the synthesis of compound 106.

Step 1: To a solution of 3-(difluoromethyl)aniline (416 mg, 2.91 mmol, 3.00 equiv.) and triethylamine (392 mg, 3.87 mmol, 4.00 equiv.) in dimethylformamide (10.0 mL) at 20°C, di(1H-imidazol-1-yl)methanone (518 mg, 3.20 mmol, 3.30 equiv.) was added in one portion. The reaction was stirred at 20°C for 1 hour, followed by the addition of a solution of 3-[6-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride VI (300 mg, 969 μmol, 1.00 equiv., hydrochloride salt) and triethylamine (196 mg, 1.94 mmol, 2.00 equiv.) in dimethylformamide (1.00 mL). The reaction was stirred at 20°C for 12 hours. The mixture was poured into saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (5 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column chromatography and reverse-phase preparative HPLC (twice) and then lyophilized to give compound 106 (118 mg, 264 μmol, 27% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.0 (s, 1H), 8.94 (s, 1H), 7.76 (s, 1H), 7.67 (s, 1H), 7.60−7.53 (m, 2H), 7.46 (dd, J = 0.8, 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.10−7.06 (m, 1H), 6.96 (s, 1H), 6.88 (t, J = 6.0 Hz, 1H), 5.11 (dd, J = 4.8, 13.2 Hz, 1H), 4.41 (s, 2H), 4.36 (dd, J = 17.2, 52.0 Hz, 2H), 2.97-2.85 (m, 1H), 2.64-2.55 (m, 1H), 2.45-2.36 (m, 1H), 2.05-1.95 (m, 1H). LCMS m/z 443.1 [M+H] ⁺

Compound 107: Prepared using General Procedure A with Variant iv) in 63% yield from Compound VI using 2-chloro-4-isocyanato-1,3,5-trimethylbenzene.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.0 (br s, 1H), 7.79 (s, 1H), 7.66 (s, 1H), 7.58 - 7.45 (m, 2H), 7.05 (s, 1H), 6.86 - 6.60 (m, 1H), 5.10 (dd, J = 5.1, 13.3 Hz, 1H), 4.50 - 4.20 (m, 4H), 2.99 - 2.82 (m, 1H), 2.65 - 2.56 (m, 1H), 2.39 (dq, J = 4.3, 13.2 Hz, 1H), 2.27 (s, 3H), 2.20 (s, 3H), 2.12 (s, 3H), 2.05 - 1.93 (m, 1H). MS (ESI) m/z 469.2 [M+H] ⁺

Scheme for the preparation of 2-chloro-4-isocyanato-1,3,5-trimethylbenzene.

Step 1: To a solution of 2-chloro-1,3,5-trimethylbenzene (2.9 g, 18.8 mmol, 1.00 equiv.) in acetic anhydride (21.0 mL) at -78°C was added a solution of nitric acid (2.53 mL, 56.3 mmol, 3.00 equiv.) in acetic anhydride (10.5 mL). The reaction was stirred at -78°C for 2 hours. Water (50.0 mL) was added to quench the reaction, and the pH was adjusted to 7 with an aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (2 x 50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 10/1) to obtain 2-chloro-1,3,5-trimethyl-4-nitrobenzene (950 mg, 4.76 mmol, 25% yield) as a white solid.

Step 2: To a solution of 2-chloro-1,3,5-trimethyl-4-nitrobenzene (950 mg, 4.76 mmol, 1.00 equiv.) in ethanol (10.0 mL) and water (3.00 mL), iron powder (797 mg, 14.3 mmol, 3.00 equiv.) and ammonium chloride (1.27 g, 23.8 mmol, 5.00 equiv.) were added. The reaction was stirred at 80°C for 12 hours. The mixture was filtered and concentrated under reduced pressure to give a residue. Water (50.0 mL) was added and the pH was adjusted to 7 with an aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (2 x 50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3-chloro-2,4,6-trimethylaniline (600 mg, 3.54 mmol, 74% yield) as a yellow oil.

Step 3: To a solution of 3-chloro-2,4,6-trimethylaniline (300 mg, 1.77 mmol, 1.00 equiv.) in toluene (10.0 mL), triphosgene (525 mg, 1.77 mmol, 1.00 equiv.) was added. The reaction was stirred at 100°C for 2 hours. The mixture was concentrated under reduced pressure to give 2-chloro-4-isocyanato-1,3,5-trimethylbenzene (345 mg, 1.76 mmol, 99% yield) as a yellow oil.

Compound 108: Scheme for the preparation of compound 108.

Step 1: To a solution of tert-butyl 4-aminopyrazole-1-carboxylate (500 mg, 2.73 mmol, 1.00 equiv.) and pyridine (0.44 mL, 5.46 mmol, 2.00 equiv.) in acetonitrile (5.00 mL) was added phenyl chloroformate (0.41 mL, 3.27 mmol, 1.20 equiv.) at 0°C. The reaction was stirred at 30°C for 2 hours. The mixture was diluted with water (15.0 mL) and extracted with ethyl acetate (2 x 20.0 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 to 5/1) and concentrated under reduced pressure to give tert-butyl 4-(phenoxycarbonylamino)pyrazole-1-carboxylate (0.60 g, 1.98 mmol, 72% yield) as a white solid.

Step 2: To a mixture of 3-[6-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride VI (500 mg, 1.61 mmol, 1.00 equiv., hydrochloride salt) and triethylamine (674 μL, 4.84 mmol, 3.00 equiv.) in dimethylformamide (5.00 mL), tert-butyl 4-(phenoxycarbonylamino)pyrazole-1-carboxylate (587 mg, 1.94 mmol, 1.20 equiv.) was added. The reaction was stirred at 30°C for 6 hours. The mixture was diluted with water (20.0 mL) and extracted with dichloromethane/isopropyl alcohol = 3/1 (3 x 30.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1 to dichloromethane/methanol = 10/1) and concentrated under reduced pressure to give tert-butyl 4-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]methylcarbamoylamino]pyrazole-1-carboxylate (550 mg, 1.14 mmol, 70% yield) as a white solid.

Step 3: To a solution of tert-butyl 4-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]methylcarbamoylamino]pyrazole-1-carboxylate (500 mg, 1.04 mmol, 1.00 equivalents) in dioxane (5.00 mL) was added hydrochloric acid/dioxane (4 M, 2.5 mL, 9.65 equivalents). The reaction was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC and lyophilized to give compound 108 (192 mg, 478 μmol, 46% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.37 (br s, 1H), 10.99 (br s, 1H), 8.28 (s, 1H), 7.64 (s, 1H), 7.54 (s, 2H), 7.50 (br s, 1H), 6.68 (br t, J = 5.6 Hz, 1H), 5.11 (dd, J = 5.2, 13.3 Hz, 1H), 4.47 - 4.26 (m, 4H), 2.97 - 2.85 (m, 1H), 2.64 - 2.55 (m, 1H), 2.45 - 2.33 (m, 1H), 2.04 - 1.94 (m, 1H). MS (ESI) m/z 383.0 [M+H] ⁺

Compound 109: Prepared using General Procedure A with Variant iii) in 17% yield from Compound VI using phenyl (3-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-5-chloro-4-methylphenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.0 (br s, 1H), 8.91 - 8.62 (m, 1H), 7.66 (s, 1H), 7.62 (d, J = 2.1 Hz, 1H), 7.56 (s, 2H), 7.06 (d, J = 2.0 Hz, 1H), 6.88 - 6.69 (m, 1H), 5.11 (dd, J = 5.0, 13.2 Hz, 1H), 4.60 (s, 4H), 4.48 - 4.27 (m, 4H), 3.44 (s, 2H), 3.30 (s, 4H), 2.97 - 2.84 (m, 1H), 2.59 (td, J = 2.0, 15.2 Hz, 1H), 2.41 (br dd, J = 8.9, 13.3 Hz, 1H), 2.17 (s, 3H), 2.04 - 1.93 (m, 1H). MS (ESI) m/z 552.2 [M+H] ⁺

Scheme for the preparation of phenyl(3-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-5-chloro-4-methylphenyl)carbamate.

Step 1: To a solution of (3-chloro-2-methyl-5-nitrophenyl)methanol (1.50 g, 7.44 mmol, 1.00 equivalents) in dichloromethane (20.0 mL) was added thionyl chloride (2.70 mL, 37.2 mmol, 5.00 equivalents) at 0°C. The reaction was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 10/1) to give 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene (1.30 g, 5.91 mmol, 79% yield) as a yellow oil.

Step 2: To a solution of 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene (900 mg, 4.09 mmol, 1.00 equiv.) in dimethylformamide (2.00 mL) was added potassium carbonate (1.13 g, 8.18 mmol, 2.00 equiv.), potassium iodide (67.9 mg, 0.41 mmol, 0.100 equiv.), and 2-oxa-6-azaspiro[3.3]heptane (811 mg, 8.18 mmol, 2.00 equiv.). The reaction was stirred at 20°C for 12 hours. The mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 3/1) to obtain 6-(3-chloro-2-methyl-5-nitrobenzyl)-2-oxa-6-azaspiro[3.3]heptane (600 mg, 2.12 mmol, 52% yield) as a white solid.

Step 3: To a solution of 6-(3-chloro-2-methyl-5-nitrobenzyl)-2-oxa-6-azaspiro[3.3]heptane (600 mg, 2.12 mmol, 1.00 equiv.) in ethanol (6.00 mL) and water (2.00 mL), iron powder (356 mg, 6.37 mmol, 3.00 equiv.) and ammonium chloride (568 mg, 10.6 mmol, 5.00 equiv.) were added. The reaction was stirred at 80°C for 2 hours. The mixture was filtered and concentrated under reduced pressure to provide a residue. Ethyl acetate (50.0 mL) was added to the residue, and the mixture was washed with a solution of saturated sodium bicarbonate (2 x 30.0 mL) and water (2 x 30.0 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-5-chloro-4-methylaniline (300 mg, 1.19 mmol, 56% yield) as a yellow solid.

Step 4: To a solution of 3-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-5-chloro-4-methylaniline (140 mg, 554 μmol, 1.00 equiv.) in dichloromethane (2.00 mL) was added dropwise pyridine (0.27 mL, 3.32 mmol, 6.00 equiv.) and a solution of phenyl chloroformate (69.4 μL, 554 μmol, 1.00 equiv.) in dichloromethane (2.00 mL) at 0°C. The reaction was stirred at 0°C for 1 hour. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 1/0 to 10/1) to obtain phenyl (3-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-5-chloro-4-methylphenyl)carbamate (180 mg, 483 μmol, 87% yield) as a yellow solid.

Compound 110: Scheme for the synthesis of compound 110.

Step 1: To a mixture of 3-aminophenol (1.00 g, 9.16 mmol, 1.00 equiv.) and sodium bicarbonate (0.43 mL, 11.0 mmol, 1.20 equiv.) in tetrahydrofuran (10.0 mL) and water (1.00 mL) was added phenyl chloroformate (1.21 mL, 9.62 mmol, 1.05 equiv.) at 0°C. The reaction was stirred at 0°C for 2 hours. The mixture was quenched with water (10.0 mL) and extracted with ethyl acetate (10.0 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give phenyl N-(3-hydroxyphenyl)carbamate (2.00 g, 8.72 mmol, 95% yield) as a white solid.

Step 2: A mixture of 3-[6-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride VI (0.800 g, 2.58 mmol, 1.00 equivalents, hydrochloride), phenyl N-(3-hydroxyphenyl)carbamate (651 mg, 2.84 mmol, 1.10 equivalents) and triethylamine (1.08 mL, 7.75 mmol, 3.00 equivalents) in dimethylformamide (10.0 mL) was heated to 50°C for 2 hours. This mixture was added dropwise to ethyl acetate (50.0 mL) at 0°C, and the resulting solid was filtered, washed with ethyl acetate (2 x 3 mL), and dried to give 1-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]methyl]-3-(3-hydroxyphenyl)urea (1.02 g, 2.50 mmol, 96% yield) as an off-white solid.

Step 3: To a mixture of 2-morpholinoacetic acid (89 mg, 612 μmol, 1.00 equiv.) and N,N-dimethylpyridin-4-amine (7.5 mg, 61.2 μmol, 0.10 equiv.) in dimethylformamide (3.00 mL) was added N,N'-methanediylidene dicyclohexanamine (136 μL, 673 μmol, 1.10 equiv.) at 0°C. The reaction was stirred at 0°C for 30 minutes, and then 1-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]methyl]-3-(3-hydroxyphenyl)urea (250 mg, 612 μmol, 1.00 equiv.) was added. The reaction was stirred at 20°C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase preparative HPLC to give compound 110 (77.4 mg, 144 μmol, 38% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1 H), 8.83 (s, 1 H), 7.67 (s, 1 H), 7.57 (s, 2 H), 7.40 (s, 1 H), 7.29 - 7.21 (m, 1 H), 7.14 (br d, J = 8.1 Hz, 1 H), 6.81 (br t, J = 5.6 Hz, 1 H), 6.66 (br d, J = 7.9 Hz, 1 H), 5.12 (br dd, J = 13.3, 5.0 Hz, 1 H), 4.49 - 4.36 (m, 3 H), 4.35 - 4.26 (m, 1 H), 3.64 - 3.56 (m, 4 H), 3.51 (s, 2 H), 2.97 - 2.85 (m, 1 H), 2.62 (br s, 1 H), 2.58 (br d, J = 4.0 Hz, 4 H), 2.46 - 2.35 (m, 1 H), 2.05 - 1.95 (m, 1 H). MS (ESI) m/z 536.2 [M+H] ⁺

Compound 111: Scheme for the synthesis of compound 111.

Step 1: A mixture of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (2.41 g, 8.63 mmol, 1.20 equiv.), 3-nitrophenol (1.43 mL, 7.19 mmol, 1.00 equiv.), and potassium carbonate (1.29 g, 9.35 mmol, 1.30 equiv.) in anhydrous dimethylformamide (20.0 mL) was stirred at 80°C under nitrogen for 8 hours. The mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (3 x 10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 to 7/1) to obtain tert-butyl 4-(3-nitrophenoxy)piperidine-1-carboxylate (1.90 g, 5.89 mmol, 81% yield) as a yellow oil.

Step 2: To a solution of tert-butyl 4-(3-nitrophenoxy)piperidine-1-carboxylate (500 mg, 1.55 mmol, 1.00 equiv.) in ethanol (10.0 mL) under a hydrogen atmosphere (15 psi), 10% wt. Pd/C on C (400 mg, 1.00 equiv.) was added. The reaction was stirred at 25°C for 6 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford tert-butyl 4-(3-aminophenoxy)piperidine-1-carboxylate (428 mg, 1.46 mmol, 94% yield) as a yellow oil.

Step 3: To a solution of tert-butyl 4-(3-aminophenoxy)piperidine-1-carboxylate (428 mg, 1.46 mmol, 1.00 equiv.) in dichloromethane (5.00 mL) at 0°C, pyridine (0.15 mL, 1.90 mmol, 1.30 equiv.) and phenyl chloroformate (0.20 mL, 1.61 mmol, 1.10 equiv.) were added. The reaction was stirred at 25°C for 3 hours. The mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (3 x 5.00 mL). The combined organic layers were washed with brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl 4-(3-((phenoxycarbonyl)amino)phenoxy)piperidine-1-carboxylate (538 mg, 1.30 mmol, 89% yield) as a yellow oil.

Step 4: To a solution of tert-butyl 4-(3-((phenoxycarbonyl)amino)phenoxy)piperidine-1-carboxylate (399 mg, 968 μmol, 1.20 equiv.) in dimethylformamide (4.00 mL) was added 3-[6-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride VI (250 mg, 807 μmol, 1.00 equiv., hydrochloride salt) and triethylamine (727 mg, 7.18 mmol, 1.00 mL, 8.90 equiv.). The reaction was stirred under nitrogen at 40°C for 2 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (3 x 15.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 25/1 to 20/1) to obtain tert-butyl 4-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)ureido)phenoxy)piperidine-1-carboxylate (327 mg, 552 μmol, 68% yield) as a yellow oil.

Step 5: A solution of tert-butyl 4-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)ureido)phenoxy)piperidine-1-carboxylate (210 mg, 354 μmol, 1.00 equiv.) in hydrochloric acid/ethyl acetate (4.00 mL) was stirred at 20°C for 0.5 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was triturated with acetonitrile at 20°C for 20 minutes to give compound 111 (75.0 mg, 152 μmol, 43% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.82 (br s, 1H), 8.68 (br s, 2H), 7.64 (s, 1H), 7.55 (s, 2H), 7.27 (s, 1H), 7.12 (t, J = 8.1 Hz, 1H), 6.89 (br s, 1H), 6.84 (br d, J = 7.9 Hz, 1H), 6.54 (dd, J = 2.1, 8.2 Hz, 1H), 5.11 (dd, J = 5.0, 13.3 Hz, 1H), 4.56 (br d, J = 3.3Hz, 1H), 4.46 - 4.36 (m, 3H), 4.33 - 4.26 (m, 1H), 3.24 - 3.15 (m, 2H), 3.11 - 3.01 (m, 2H), 2.96 - 2.84 (m, 1H), 2.59 (br d, J = 18.3 Hz, 1H), 2.42 - 2.30 (m, 1H), 2.10 - 1.95 (m, 3H), 1.83 (br d, J = 3.5 Hz, 2H). MS (ESI) m/z 492.2 [M+H] ⁺

Compound 112: Prepared using General Procedure A with Variant iii) in 29% yield from Compound VI using phenyl (3-(1H-imidazol-2-yl)phenyl)carbamate.

¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.00 (br s, 1H), 8.80 (s, 1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.68 (s, 1H), 7.61 - 7.52 (m, 2H), 7.46 - 7.36 (m, 2H), 7.31 - 7.23 (m, 1H), 7.09 (br s, 2H), 6.86 (t, J = 6.0 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.37 (m, 3H), 4.34 - 4.25 (m, 1H), 2.97 - 2.83 (m, 1H), 2.58 (br dd, J = 2.2, 15.3 Hz, 1H), 2.42 - 2.33 (m, 1H), 2.03 - 1.94 (m, 1H). MS (ESI) m/z 459.1 [M+H] ⁺

Scheme for the preparation of phenyl(3-(1H-imidazol-2-yl)phenyl)carbamate.

Step 1: To a mixture of 2-(3-nitrophenyl)-1H-imidazole (900 mg, 4.76 mmol, 1.00 equiv.), di-tert-butyl dicarbonate (1.64 mL, 7.14 mmol, 1.50 equiv.), and 4-dimethylaminopyridine (58.1 mg, 475 μmol, 0.10 equiv.) in dichloromethane (9.00 mL), triethylamine (993 μL, 7.14 mmol, 1.50 equiv.) was added and the reaction was stirred at 25°C for 16 hours. The mixture was diluted with water (10.0 mL) and extracted with dichloromethane (3 x 10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain tert-butyl 2-(3-nitrophenyl)-1H-imidazole-1-carboxylate (1.12 g, 3.87 mmol, 81% yield) as a yellow oil.

Step 2: To a solution of tert-butyl 2-(3-nitrophenyl)-1H-imidazole-1-carboxylate (500 mg, 1.73 mmol, 1.00 equivalent) in ethyl alcohol (10.0 mL), 10% by weight of Pd/C supported on C (400 mg, 1.73 mmol, 1.00 equivalent) was added, and the mixture was stirred under a hydrogen atmosphere (15 psi) at 25°C for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 2-(3-aminophenyl)-1H-imidazole-1-carboxylate (842 mg, 3.25 mmol, 93% yield) as a yellow solid.

Step 3: To a solution of tert-butyl 2-(3-aminophenyl)-1H-imidazole-1-carboxylate (790 mg, 3.05 mmol, 1.00 equiv.) in dichloromethane (10.0 mL) at 0°C, pyridine (0.32 mL, 3.96 mmol, 1.30 equiv.) and phenyl chloroformate (524 mg, 3.35 mmol, 419 μL, 1.10 equiv.) were added. The reaction was stirred at 25°C for 3 hours. The mixture was diluted with water (50.0 mL) and extracted with dichloromethane (3 x 50.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give phenyl (3-(1H-imidazol-2-yl)phenyl)carbamate (740 mg, 2.65 mmol, 86% yield) as a yellow solid.

Compound 113: Prepared using General Procedure A with Variant iii) in 68% yield from Compound VI using phenyl (3-(2-methyl-1H-imidazol-1-yl)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 8.96 (s, 1H), 8.15 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 7.59 - 7.54 (m, 2H), 7.37 (d, J = 4.6 Hz, 2H), 7.26 (s, 1H), 6.99 - 6.88 (m, 3H), 5.11 (dd, J = 5.1, 13.5 Hz, 1H), 4.46 - 4.38 (m, 3H), 4.33 - 4.28 (m, 1H), 2.97 - 2.85 (m, 1H), 2.60 (br d, J MS (ESI) m/z 473.1 [M+H] ⁺

Scheme for the preparation of phenyl(3-(2-methyl-1H-imidazol-1-yl)phenyl)carbamate.

Step 1: To a solution of 3-(2-methylimidazol-1-yl)aniline (90.0 mg, 520 μmol, 1.00 equiv) in dichloromethane (3.00 mL) was added pyridine (84 μL, 1.04 mmol, 2.00 equiv). To this mixture was added phenyl chloroformate (72 μL, 572 μmol, 1.10 equiv) in small portions. The reaction was stirred at 20° C. for 2 hours. The mixture was poured into water (5.00 mL) and extracted with dichloromethane (2×5.00 mL). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (ethyl acetate/methanol=10/1, R _f =0.55) to give phenyl (3-(2-methyl-1H-imidazol-1-yl)phenyl)carbamate (140 mg, crude product) as a white solid. It was used as is in the next reaction.

Compound 114: Prepared using General Procedure A with Variant iii) in 62% yield from Compound VI using phenyl(4-(difluoromethyl)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.93 (s, 1H), 7.67 (s, 1H), 7.58 - 7.48 (m, 4H), 7.42 (d, J = 8.4 Hz, 2H), 7.07 - 6.73 (m, 2H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.37 (m, 3H), 4.36 - 4.25 (m, 1H), 2.91 (ddd, J = 5.4, 13.5, 17.5 Hz, 1H), 2.62 - 2.57 (m, 1H), 2.39 (br dd, J = 4.5, 13.1 Hz, 1H), 2.04 - 1.95 (m, 1H). MS (ESI) m/z 423.3 [M-20] ⁺

Scheme for the preparation of phenyl(4-(difluoromethyl)phenyl)carbamate.

Step 1: To a solution of 4-(difluoromethyl)aniline hydrochloride (400 mg, 2.23 mmol, 1.00 equiv.) in tetrahydrofuran (8.00 mL), triethylamine (0.62 mL, 4.45 mmol, 2.00 equiv.) and phenyl chloroformate (0.31 mL, 2.45 mmol, 1.10 equiv.) were added. The reaction was stirred at 20°C for 1 hour. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 5/1) to give phenyl (4-(difluoromethyl)phenyl)carbamate (440 mg, 1.67 mmol, 75% yield) as a white solid.

Compound 115: Prepared using General Procedure A with Variant iii) in 37% yield from Compound VI using phenyl (3-(1-methyl-1H-pyrazol-5-yl)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.81 (s, 1H), 7.67 (s, 1H), 7.61 (s, 1H), 7.59 - 7.55 (m, 2H), 7.46 - 7.41 (m, 2H), 7.37 - 7.31 (m, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.84 (t, J = 6.1 Hz, 1H), 6.35 (d, J = 1.8 Hz, 1H), 5.11 (dd, J = 5.1, 13.2 Hz, 1H), 4.47 - 4.39 (m, 3H), 4.34 - 4.27 MS (ESI) m/z 473.1 [M+H] ⁺

Scheme for the preparation of phenyl(3-(1-methyl-1H-pyrazol-5-yl)phenyl)carbamate.

Step 1: To a mixture of 5-bromo-1-methyl-pyrazole (0.500 g, 3.11 mmol, 1.00 equiv.) and (3-aminophenyl)boronic acid (510 mg, 3.73 mmol, 1.20 equiv.) in dioxane (10.0 mL) and water (1.00 mL), tetrakis(triphenylphosphine)palladium (359 mg, 311 μmol, 0.10 equiv.) and potassium phosphate (1.98 g, 9.32 mmol, 3.0 equiv.) were added. The reaction was stirred at 110°C for 16 hours. The mixture was poured into water (20.0 mL), and the product was extracted with ethyl acetate (2 x 20.0 mL). The combined organic layers were washed with brine (10.0 mL) and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1 to 1/1) to obtain 3-(2-methylpyrazol-3-yl)aniline (400 mg, 2.15 mmol, 69% yield) as a yellow oil.

Step 2: To a solution of 3-(2-methylpyrazol-3-yl)aniline (0.400 g, 2.31 mmol, 1.00 equiv.) in dichloromethane (5.00 mL) was added pyridine (0.34 mL, 4.62 mmol, 2.00 equiv.). The mixture was cooled to 0°C, and phenyl chloroformate (0.32 mL, 2.54 mmol, 1.10 equiv.) was added dropwise. The reaction was stirred at 20°C for 1 hour. Water (5.00 mL) was added to the mixture. The organic layer was separated, washed with brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give phenyl (3-(1-methyl-1H-pyrazol-5-yl)phenyl)carbamate (650 mg, crude) as a yellow oil, which was used directly in the next reaction.

Compound 116: Prepared using General Procedure A with Variant iii) in 33% yield from Compound VI using phenyl N-[3-(1-methylpyrazol-3-yl)phenyl]carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.98 (br s, 1 H), 8.70 (br s, 1 H), 7.89 (br s, 1 H), 7.76 - 7.65 (m, 2 H), 7.58 (br s, 2 H), 7.39 - 7.18 (m, 3 H), 6.74 (br s, 1 H), 6.58 (br d, J = 2.1 Hz, 1 H), 5.12 (br dd, J = 13.1, 4.9 Hz, 1 H), 4.49 - 4.26 (m, 4 H), 3.88 (s, 3 H), 2.99 - 2.83 (m, 1 H), 2.60 (br d, J = 17.4 Hz, 1 H), 2.45 - 2.36 (m, 1 H), 2.07 - 1.94 (m, 1 H). MS (ESI) m/z 473.2 [M+H] ⁺

Scheme for the preparation of phenyl N-[3-(1-methylpyrazol-3-yl)phenyl]carbamate.

Step 1: A mixture of 3-bromo-1-methyl-pyrazole (0.550 g, 3.42 mmol, 1.00 equiv.), (3-aminophenyl)boronic acid (561 mg, 4.10 mmol, 1.20 equiv.), potassium phosphate (2.18 g, 10.3 mmol, 3.00 equiv.), and tetrakis(triphenylphosphine)palladium (197 mg, 171 μmol, 0.05 equiv.) in dioxane (10.0 mL) and water (1.00 mL) was heated to 110°C under nitrogen for 16 hours. Water (10.0 mL) was added to the mixture, which was then extracted with ethyl acetate (2 x 10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC to give 3-(1-methylpyrazol-3-yl)aniline (0.410 g, 2.37 mmol, 69% yield) as a yellow solid.

Step 2: To a solution of 3-(1-methylpyrazol-3-yl)aniline (0.380 g, 2.19 mmol, 1.00 equiv.) and pyridine (0.53 mL, 6.58 mmol, 3.00 equiv.) in dichloromethane (10.0 mL) was added phenyl chloroformate (0.30 mL, 2.41 mmol, 1.10 equiv.) at 0°C. The mixture was warmed to 20°C and stirred for 2 hours. Water (10.0 mL) was added, and the organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give phenyl N-[3-(1-methylpyrazol-3-yl)phenyl]carbamate (0.600 g, 2.05 mmol, 93% yield) as a yellow solid, which was used directly in the next step.

Compound 117: Prepared using General Procedure A with Variant iii) in 37% yield from Compound VI using (3-chloro-5-(3-(dimethylamino)propoxy)-4-methylphenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 8.91 (s, 1H), 8.23 (s, 1H), 7.66 (s, 1H), 7.56 (d, J = 1.0 Hz, 2H), 7.15 (d, J = 1.9 Hz, 1H), 7.05 (d, J = 1.8 Hz, 1H), 7.03 - 6.89 (m, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.42 - 4.30 (m, 4H), 3.98 - 3.94 (m, 2H), 2.95 - 2.88 (m, 1H), 2.63 - 2.58 (m, 1H), 2.47 - 2.44 (m, 2H), 2.42 - 2.36 (m, 1H), 2.21 (s, 6H), 2.11 (s, 3H), 2.03 - 1.97 (m, 1H), 1.89 (t, J = 6.8 Hz, 2H). MS (ESI) m/z 542.2 [M+H] ⁺

Scheme for the preparation of (3-chloro-5-(3-(dimethylamino)propoxy)-4-methylphenyl)carbamate.

Step 1: A mixture of methyl 3-chloro-5-hydroxy-4-methylbenzoate (1.00 g, 4.98 mmol, 1.00 equiv.), 3-chloro-N,N-dimethyl-propan-1-amine hydrochloride (709 mg, 4.49 mmol, 0.90 equiv., hydrochloride salt), and potassium carbonate (2.07 g, 14.9 mmol, 3.00 equiv.) in acetonitrile (20.0 mL) was stirred at 85°C for 12 hours. The mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layers were washed with brine (3 x 10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC to give methyl 3-chloro-5-(3-(dimethylamino)propoxy)-4-methylbenzoate (1.00 g, 3.50 mmol, 70% yield) as a yellow oil.

Step 2: To a solution of methyl 3-chloro-5-(3-(dimethylamino)propoxy)-4-methylbenzoate (900 mg, 3.15 mmol, 1.00 equiv.) in water (10.0 mL) and methanol (20.0 mL), sodium hydroxide (252 mg, 6.30 mmol, 2.00 equiv.) was added. The reaction was stirred at 60°C for 2 hours. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase preparative HPLC to provide 3-chloro-5-(3-(dimethylamino)propoxy)-4-methylbenzoic acid (750 mg, 2.76 mmol, 87% yield) as a yellow solid.

Step 3: To a mixture of 3-chloro-5-(3-(dimethylamino)propoxy)-4-methylbenzoic acid (600 mg, 2.21 mmol, 1.00 equiv.) and triethylamine (614 μL, 4.42 mmol, 2.00 equiv.) in 2-methylpropan-2-ol (10.0 mL), diphenylphosphoryl azide (0.96 mL, 4.42 mmol, 2.00 equiv.) was added. The reaction was stirred at 100°C for 12 hours. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase preparative HPLC to provide tert-butyl (3-chloro-5-(3-(dimethylamino)propoxy)-4-methylphenyl)carbamate (360 mg, 1.05 mmol, 47% yield) as a yellow oil.

Step 4: A solution of tert-butyl (3-chloro-5-(3-(dimethylamino)propoxy)-4-methylphenyl)carbamate (350 mg, 1.02 mmol, 1.00 equiv.) in hydrogen chloride/ethyl acetate (4.00 M, 10.0 mL, 39.2 equiv.) was stirred at 25°C for 0.5 hours. The mixture was concentrated under reduced pressure to give 3-chloro-5-(3-(dimethylamino)propoxy)-4-methylaniline (360 mg, crude, hydrogen chloride) as a yellow solid, which was used directly in the next step.

Step 5: To a solution of 3-chloro-5-(3-(dimethylamino)propoxy)-4-methylaniline (300 mg, 1.07 mmol, 1.00 equivalents, hydrogen chloride) and triethylamine (326 mg, 3.22 mmol, 3.00 equivalents) in dichloromethane (5.00 mL) was added phenyl chloroformate (252 mg, 1.61 mmol, 1.50 equivalents) at 25°C. The mixture was stirred at 25°C for 0.5 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC and lyophilized to give phenyl (3-chloro-5-(3-(dimethylamino)propoxy)-4-methylphenyl)carbamate (150 mg, 0.41 mmol, 38% yield) as a yellow oil.

Compound 118: Prepared using General Procedure A with Variant iii) in 60% yield from Compound VI using phenyl N-[3,4-dimethyl-5-(morpholinomethyl)phenyl]carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.43 (s, 1H), 8.15 (s, 1H), 7.65 (s, 1H), 7.55 (d, J = 0.8 Hz, 2H), 7.17 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.65 (t, J = 6.0 Hz, 1H), 5.11 (dd, J = 5.2, 13.2 Hz, 1H), 4.46 - 4.28 (m, 4H), 3.54 (br t, J = 4.0 Hz, 4H), 3.34 (s, 2H), 2.97 - 2.85 (m, 1H), 2.59 (br d, J = 17.4 Hz, 1H), 2.45 - 2.38 (m, 1H), 2.34 (br s, 4H), 2.17 (s, 3H), 2.12 (s, 3H), 2.04 - 1.95 (m, 1H). MS (ESI) m/z 520.2 [M+H] ⁺

Scheme for the preparation of phenyl N-[3,4-dimethyl-5-(morpholinomethyl)phenyl]carbamate.

Step 1: To a solution of sodium hydroxide (2.19 g, 54.8 mmol, 3.00 equiv.) in water (10.0 mL) and ethanol (10.0 mL), methyl 2,3-dimethylbenzoate (3.00 g, 18.3 mmol, 1.00 equiv.) was added in one portion. The reaction was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure and poured into water (50.0 mL). The pH was adjusted to pH = 1-2 with 36% aqueous hydrochloric acid, and the mixture was filtered. The filter cake was washed with water (2 x 20.0 mL) and dried under reduced pressure to give 2,3-dimethylbenzoic acid (2.50 g, 16.6 mmol, 91% yield) as a white solid.

Step 2: To a solution of 2,3-dimethylbenzoic acid (2.50 g, 16.6 mmol, 1.00 equiv.) in sulfuric acid (25.0 mL) at 0°C, potassium nitrate (2.02 g, 19.98 mmol, 1.20 equiv.) was added in small portions. The reaction was warmed to 15°C and stirred for 12 hours. The mixture was poured into ice-water (200 mL) and filtered, and the filter cake was washed with water (2 x 50.0 mL). The filter cake was dried under reduced pressure to give 2,3-dimethyl-5-nitrobenzoic acid (3.00 g, 15.4 mmol, 92% yield) as a white solid.

Step 3: To a solution of 2,3-dimethyl-5-nitrobenzoic acid (4.50 g, 23.1 mmol, 1.00 equiv.) in tetrahydrofuran (100 mL) at 20°C, dimethylsulfide borane (10.0 M, 4.61 mL, 2.00 equiv.) was added dropwise. The reaction was heated to 60°C and stirred for 5 hours. The mixture was cooled to 0°C and then quenched with methanol (5.00 mL) and water (5.00 mL) and stirred at 20°C for 0.5 hours. The mixture was concentrated under reduced pressure and poured into saturated aqueous sodium bicarbonate (50.0 mL). The mixture was extracted with ethyl acetate (4 x 50.0 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 7/3) to obtain (2,3-dimethyl-5-nitrophenyl)methanol (2.50 g, 13.80 mmol, 59% yield) as a yellow solid.

Step 4: To a solution of (2,3-dimethyl-5-nitrophenyl)methanol (2.50 g, 13.8 mmol, 1.00 equiv.) in dichloromethane (20.0 mL) at 0°C, thionyl chloride (10.0 mL, 138 mmol, 10.0 equiv.) and N-methylpyrrolidone (1.34 mL, 13.8 mmol, 1.00 equiv.) were added dropwise. The reaction was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. Acetonitrile (20.0 mL) was added, followed by triethylamine (5.76 mL, 41.4 mmol, 3.00 equiv.) and morpholine (1.46 mL, 16.5 mmol, 1.20 equiv.). The reaction was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 0/1) to obtain 4-[(2,3-dimethyl-5-nitrophenyl)methyl]morpholine (2.50 g, 9.79 mmol, 70% yield) as a yellow solid.

Step 5: To a solution of 4-[(2,3-dimethyl-5-nitrophenyl)methyl]morpholine (2.50 g, 10.0 mmol, 1.00 equiv.) in ethanol (30.0 mL) and water (15.0 mL) at 20°C, ammonium chloride (534 mg, 10.0 mmol, 1 equiv.) and iron powder (2.79 g, 50.0 mmol, 5.00 equiv.) were added in small portions. The reaction was stirred at 90°C for 12 hours. The mixture was filtered, and the filter cake was washed with methanol (50.0 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was poured into saturated aqueous sodium bicarbonate (50.0 mL) and extracted with ethyl acetate (4 x 50.0 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3,4-dimethyl-5-(morpholinomethyl)aniline (2.10 g, 9.53 mmol, 95% yield) as a yellow solid.

Step 6: To a solution of 3,4-dimethyl-5-(morpholinomethyl)aniline (1.00 g, 4.54 mmol, 1.00 equivalents) and triethylamine (1.26 mL, 9.08 mmol, 2.00 equivalents) in tetrahydrofuran (10.0 mL) was added dropwise phenyl chloroformate (0.68 mL, 5.45 mmol, 1.20 equivalents) at 20°C. The reaction mixture was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate/methanol = 1/0 to 10/1) to give phenyl N-[3,4-dimethyl-5-(morpholinomethyl)phenyl]carbamate (600 mg, 1.67 mmol, 36% yield) as a yellow solid.

Compound 119: Prepared using General Procedure A with Variant iii) in 24% yield from Compound VI using phenyl N-[3-chloro-5-(morpholinomethyl)phenyl]carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.92 (s, 1H), 8.15 (s, 1H), 7.69 - 7.53 (m, 4H), 7.19 (s, 1H), 6.92 - 6.81 (m, 2H), 5.11 (dd, J = 5.2, 13.2 Hz, 1H), 4.48 - 4.27 (m, 4H), 3.60 - 3.53 (m, 4H), 3.39 (s, 2H), 2.98 - 2.82 (m, 1H), 2.64 - 2.56 (m, 1H), 2.45 - 2.37 (m, 1H), 2.34 (br s, 4H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 526.1 [M+H] ⁺

Scheme for the preparation of phenyl N-[3-chloro-5-(morpholinomethyl)phenyl]carbamate.

Step 1: To a solution of (3-chloro-5-nitrophenyl)methanol (880 mg, 4.69 mmol, 1.00 equiv.) and N-methylpyrrolidone (1.50 mL) in dichloromethane (10.0 mL) was added thionyl chloride (3.4 mL, 46.9 mmol, 10.0 equiv.) at 0°C. The reaction was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with saturated aqueous sodium bicarbonate (60.0 mL) and extracted with ethyl acetate (4 x 50.0 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to give 1-chloro-3-(chloromethyl)-5-nitrobenzene (1.49 g, crude) as a yellow liquid.

Step 2: To a solution of 1-chloro-3-(chloromethyl)-5-nitrobenzene (1.40 g, 6.80 mmol, 1.00 equivalents) in acetonitrile (17.0 mL), triethylamine (2.36 mL, 17.0 mmol, 2.50 equivalents) and morpholine (0.78 mL, 8.83 mmol, 1.30 equivalents) were added. The reaction was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 7/1) to give 4-[(3-chloro-5-nitrophenyl)methyl]morpholine (1.0 g, 3.90 mmol, 57% yield) as a yellow liquid.

Step 3: To a solution of 4-[(3-chloro-5-nitrophenyl)methyl]morpholine (980 mg, 3.82 mmol, 1.00 equiv.) in ethanol (16.0 mL) and water (8.00 mL), ammonium chloride (204 mg, 3.82 mmol, 1.00 equiv.) and iron powder (1.07 g, 19.1 mmol, 5.00 equiv.) were added. The reaction was stirred at 90°C for 12 hours. The mixture was filtered and washed with ethyl acetate (20.0 mL), and the filtrate was extracted with ethyl acetate (3 x 20.0 mL). The combined organic layers were washed with brine (25.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 3-chloro-5-(morpholinomethyl)aniline (730 mg, 3.22 mmol, 84% yield) as a yellow liquid.

Step 4: To a solution of phenyl chloroformate (0.21 mL, 1.70 mmol, 1.10 equiv.) in tetrahydrofuran (20.0 mL), triethylamine (0.43 mL, 3.09 mmol, 2.00 equiv.) and 3-chloro-5-(morpholinomethyl)aniline (350 mg, 1.54 mmol, 1.00 equiv.) were added. The mixture was stirred at 25°C for 0.5 hours. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to give phenyl N-[3-chloro-5-(morpholinomethyl)phenyl]carbamate (460 mg, 1.33 mmol, 85% yield) as a yellow solid.

Compound 120: Scheme for the synthesis of compound 120.

Step 1: To a solution of 3-chloro-4-methyl-benzoic acid (20.0 g, 117 mmol, 1.00 equiv.) in sulfuric acid (80.0 mL) was added 1-iodopyrrolidine-2,5-dione (29.0 g, 129 mmol, 1.10 equiv.). The reaction was stirred at 25°C for 1 hour. The mixture was slowly poured into stirred ice-water (300 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL) and dried under reduced pressure. Methanol (200 mL) was added, and the mixture was concentrated under reduced pressure to give 3-chloro-5-iodo-4-methyl-benzoic acid (36.0 g, crude) as a white solid, which was used directly in the next step.

Step 2: To a solution of 3-chloro-5-iodo-4-methylbenzoic acid (34.8 g, 117 mmol, 1.00 equiv.) in methanol (500 mL) was added thionyl chloride (27.9 g, 234 mmol, 17.0 mL, 2.00 equiv.) dropwise at 0°C. The reaction was stirred at 60°C for 12 hours. The mixture was concentrated to 100 mL under reduced pressure, and the resulting suspension was filtered. The filter cake was washed with methanol (30.0 mL) and dried under reduced pressure to give methyl 3-chloro-5-iodo-4-methylbenzoate (31.0 g, 99.8 mmol, 85% yield) as a white solid.

Step 3: A solution of methyl 3-chloro-5-iodo-4-methylbenzoate (10.0 g, 32.2 mmol, 1.00 equiv.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (16.4 g, 64.4 mmol, 2.00 equiv.), potassium acetate (9.48 g, 96.6 mmol, 3.00 equiv.), and (1,1-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (2.36 g, 3.22 mmol, 0.10 equiv.) in dioxane (200 mL) was stirred at 110°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a residue. This residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 100/5) to give a residue. The residue was triturated with petroleum ether (100 mL) and filtered. The filter cake was washed with petroleum ether (50.0 mL) and dried under reduced pressure to give methyl 3-chloro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (6.00 g, 19.3 mmol, 60% yield) as a white solid.

Step 4: To a solution of tert-butyl 2-bromoacetate (0.79 mL, 5.37 mmol, 1.00 equiv.), palladium acetate (36.1 mg, 161 μmol, 0.03 equiv.), potassium phosphate (5.70 g, 26.8 mmol, 5.00 equiv.), and tris-o-tolylphosphane (147 mg, 483 μmol, 0.09 equiv.) in tetrahydrofuran (40.0 mL) was added methyl 3-chloro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.00 g, 6.44 mmol, 1.20 equiv.). The reaction was stirred under nitrogen at 25°C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 5/1) to give a residue. The residue was triturated with petroleum ether (10.0 mL) and filtered. The filtrate was concentrated to give methyl 3-(2-tert-butoxy-2-oxo-ethyl)-5-chloro-4-methyl-benzoate (400 mg, crude) as a clear oil, which was used directly in the next step.

Step 5: To a solution of methyl 3-(2-tert-butoxy-2-oxoethyl)-5-chloro-4-methylbenzoate (400 mg, 1.34 mmol, 1.00 equivalents) in methanol (3.00 mL) was added a solution of sodium hydroxide (107 mg, 2.68 mmol, 2.00 equivalents) in water (3.00 mL). The reaction was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with 1M hydrochloric acid (3.00 mL) and extracted with ethyl acetate (50.0 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 3-(2-(tert-butoxy)-2-oxoethyl)-5-chloro-4-methylbenzoic acid (350 mg, crude) as a white solid, which was used directly in the next step.

Step 6: To a solution of 3-(2-tert-butoxy-2-oxo-ethyl)-5-chloro-4-methyl-benzoic acid (300 mg, 1.05 mmol, 1.00 equiv.) and triethylamine (0.16 mL, 1.16 mmol, 1.10 equiv.) in toluene (3.00 mL) was added diphenylphosphoryl azide (0.25 mL, 1.16 mmol, 1.10 equiv.). The reaction was stirred at 20°C for 10 minutes, and then phenol (0.46 mL, 5.27 mmol, 5.00 equiv.) was added. The reaction was stirred at 100°C for 30 minutes. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 5/1) to obtain tert-butyl 2-(3-chloro-2-methyl-5-((phenoxycarbonyl)amino)phenyl)acetate (150 mg, 399 μmol, 38% yield) as a white solid.

Step 7: To a solution of 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride VI (150 mg, 484 μmol, 1.00 equiv., hydrochloride salt) and triethylamine (135 μL, 969 μmol, 2.00 equiv.) in dimethylformamide (2.00 mL) was added tert-butyl 2-(3-chloro-2-methyl-5-((phenoxycarbonyl)amino)phenyl)acetate (182 mg, 484 μmol, 1.00 equiv.). The reaction was stirred at 25°C for 12 hours. This mixture was purified by reverse-phase column chromatography and lyophilized to obtain tert-butyl 2-(3-chloro-5-(3-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)ureido)-2-methylphenyl)acetate (250 mg, 450 μmol, 93% yield) as a white solid.

Step 8: To a solution of tert-butyl 2-(3-chloro-5-(3-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)ureido)-2-methylphenyl)acetate (240 mg, 432 μmol, 1.00 equivalents) in dichloromethane (5.00 mL) was added trifluoroacetic acid (5.00 mL). The reaction was stirred at 20°C for 1 hour. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase preparative HPLC and lyophilized to provide compound 120 (81.1 mg, 161 μmol, 37% yield) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 12.42 (br s, 1H), 10.98 (s, 1H), 8.71 (s, 1H), 7.66 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.56 (s, 2H), 7.08 (d, J = 1.8 Hz, 1H), 6.79 (br t, J = 5.7 Hz, 1H), 5.11 (dd, J = 5.3, 13.4 Hz, 1H), 4.48 - 4.27 (m, 4H), 3.60 (s, 2H), 2.97 - 2.84 (m, 1H), 2.62 - 2.58 (m, 1H), 2.41 - 2.37 (m, 1H), 2.17 (s, 3H), 2.04 - 1.93 (m, 1H). MS (ESI) m/z 499.1 [M+H] ⁺

Compound 121: Prepared using General Procedure A with Variant iii) in 43% yield from Compound VI using phenyl(3-(pyridin-2-yloxy)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.00 (s, 1 H), 8.80 (s, 1 H), 8.17 (dd, J = 4.9, 1.8 Hz, 1 H), 7.79 - 7.89 (m, 1 H), 7.66 (s, 1 H), 7.56 (s, 2 H), 7.34 (t, J = 2.0 Hz, 1 H), 7.20 - 7.29 (m, 1 H), 7.10 - 7.16 (m, 2 H), 7.00 (d, J = 8.3 Hz, 1 H), 6.75 - 6.82 (m, 1 H), 6.65 (dd, J = 8.0, 1.7Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1 H), 4.28 - 4.47 (m, 4 H), 2.85 - 2.98 (m, 1 H), 2.60 (br d, J = 16.5 Hz, 1 H), 2.35 - 2.47 (m, 1 H), 1.94 - 2.05 (m, 1 H). MS (ESI) m/z 486.1 [M+H] ⁺

Scheme for the preparation of phenyl(3-(pyridin-2-yloxy)phenyl)carbamate.

Step 1: To a solution of 3-(pyridin-2-yloxy)aniline (0.250 g, 1.34 mmol, 1.00 equiv.) and triethylamine (0.56 mL, 4.03 mmol, 3.00 equiv.) in dichloromethane (5.00 mL) was added dropwise phenyl chloroformate (185 μL, 1.48 mmol, 1.10 equiv.) at 0°C. The reaction was stirred at 20°C for 3 hours. Water (5.00 mL) was added, and the organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give phenyl(3-(pyridin-2-yloxy)phenyl)carbamate (0.200 g, 653 μmol, 49% yield) as a white solid.

Compound 122: Prepared using General Procedure A with Variant iii) in 68% yield from Compound VI using phenyl (3-chloro-4-methyl-5-morpholinophenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (br s, 1H), 8.76 (s, 1H), 7.65 (s, 1H), 7.56 (s, 2H), 7.37 (d, J = 2.0 Hz, 1H), 7.00 (d, J = 1.8 Hz, 1H), 6.80 (t, J = 6.1 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.35 (m, 3H), 4.34 - 4.25 (m, 1H), 3.76 - 3.66 (m, 4H), 2.98 - 2.84 (m, 1H), 2.82 - 2.71 (m, 4H), 2.68 - 2.55 (m, 1H), 2.39 - 2.31 (m, 1H), 2.19 (s, 3H), 2.06 - 1.91 (m, 1H). MS (ESI) m/z 526.3 [M+H] ⁺

Scheme for the preparation of phenyl(3-chloro-4-methyl-5-morpholinophenyl)carbamate.

Step 1: To a solution of methyl 3-chloro-5-iodo-4-methylbenzoate (4.00 g, 12.9 mmol, 1.00 equiv.) in toluene (40.0 mL) under nitrogen, morpholine (1.36 mL, 15.5 mmol, 1.20 equiv.) and cesium carbonate (21.0 g, 64.4 mmol, 5.00 equiv.) were added. Separate solutions of palladium acetate (289 mg, 1.29 mmol, 0.10 equiv.) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (802 mg, 1.29 mmol, 0.10 equiv.) in toluene (20.0 mL) were added. The reaction was stirred at 120°C for 12 hours. The mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 10/1) to obtain methyl 3-chloro-4-methyl-5-morpholinobenzoate (1.35 g, 5.01 mmol, 39% yield) as an orange oil.

Step 2: To a solution of methyl 3-chloro-4-methyl-5-morpholinobenzoate (1.55 g, 5.75 mmol, 1.00 equiv.) in tetrahydrofuran (15.0 mL) and water (5.00 mL), lithium hydroxide (275 mg, 11.5 mmol, 2.00 equiv.) was added. The reaction was stirred at 20°C for 12 hours. Water (20.0 mL) was added, and the mixture was extracted with ethyl acetate (2 x 25.0 mL). The pH of the aqueous layer was adjusted to pH = 7 by adding 1 M hydrochloric acid, and it was extracted with ethyl acetate (2 x 30.0 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 3-chloro-4-methyl-5-morpholinobenzoic acid (1.30 g, 5.08 mmol, 88% yield) as a white solid.

Step 3: To a solution of 3-chloro-4-methyl-5-morpholinobenzoic acid (600 mg, 2.35 mmol, 1.00 equiv.) and triethylamine (0.36 mL, 2.58 mmol, 1.10 equiv.) in toluene (6.00 mL), diphenylphosphoryl azide (0.56 mL, 2.58 mmol, 1.10 equiv.) was added. The reaction was stirred at 20°C for 10 minutes. Next, phenol (1.03 mL, 11.7 mmol, 5.00 equiv.) was added, and the reaction was stirred at 100°C for 30 minutes. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 3/1) to give phenyl (3-chloro-4-methyl-5-morpholinophenyl)carbamate (695 mg, 2.00 mmol, 85% yield) as a white solid.

Compound 123: Prepared using General Procedure A with Variant iii) in 3% yield from Compound VI using phenylpyridin-2-ylcarbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.20 (s, 1H), 10.97 (s, 1H), 8.30 (s, 1H), 8.23 (dd, J = 1.2, 5.6 Hz, 1H), 8.09 (t, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.62−7.55 (m, 2H), 7.41 (d, J = 8.8 Hz, 1H), 7.22 (t, J = 6.4 Hz, 1H), 5.10 (dd, J = 4.8 Hz, 13.2 Hz, 1H), 4.50 (m, J = 5.6 Hz, 2H), 4.37 (dd, J = 17.2, LCMS m/z 394.0 [M+H] ⁺

Scheme for the preparation of phenylpyridin-2-ylcarbamates.

To a solution of pyridin-2-amine (2.00 g, 21.3 mmol, 1.00 equiv.) in tetrahydrofuran (50.0 mL), phenyl chloroformate (3.66 g, 23.4 mmol, 1.10 equiv.) and triethylamine (4.30 g, 42.5 mmol, 2.00 equiv.) were added. The reaction was stirred at 25°C for 0.5 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column chromatography to give phenylpyridin-2-ylcarbamate (220 mg, 975 μmol, 4% yield) as a white solid.

Compound 124: Prepared using General Procedure A with Variant iii) in 80% yield from Compound VI using phenyl (3-chloro-4-methyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 8.80 (br s, 1H), 8.25 - 8.14 (m, 1H), 7.74 - 7.62 (m, 2H), 7.56 (s, 2H), 7.11 (d, J = 1.8 Hz, 1H), 6.83 (br s, 1H), 5.12 (dd, J = 5.0, 13.2 Hz, 1H), 4.55 - 4.23 (m, 4H), 3.38 (s, 2H), 3.00 - 2.85 (m, 1H), 2.69 - 2.56 (m, 2H), 2.47 - 2.29 (m, 8H), 2.25 (s, 3H), 2.19 (s, 3H), 2.07 - 1.94 (m, 1H). MS (ESI) m/z 553.3 [M+H] ⁺

Scheme for the preparation of phenyl(3-chloro-4-methyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)carbamate.

Step 1: To a solution of (3-chloro-2-methyl-5-nitrophenyl)methanol (2.00 g, 9.92 mmol, 1.00 equiv.) in dichloromethane (20.0 mL) was added thionyl chloride (5.90 g, 49.6 mmol, 3.60 mL, 5.00 equiv.) dropwise. The reaction was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to give 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene (2.20 g, 10.0 mmol, crude) as a gray solid. To a solution of 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene (2.20 g, 10.00 mmol, 1.00 equiv) and triethylamine (3.48 mL, 25.0 mmol, 2.50 equiv) in acetonitrile (20.0 mL) was added 1-methylpiperazine (1.44 mL, 13.0 mmol, 1.30 equiv). The reaction was stirred at 25° C. for 10 hours. The mixture was diluted with water (6.00 mL) and extracted with ethyl acetate (3×25.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 1/1) to obtain 1-(3-chloro-2-methyl-5-nitrobenzyl)-4-methylpiperazine (0.70 g, 2.47 mmol, 25% yield) as a yellow solid.

Step 2: A mixture of 1-(3-chloro-2-methyl-5-nitrobenzyl)-4-methylpiperazine (0.70 g, 2.47 mmol, 1.00 equiv.), ammonium chloride (132 mg, 2.47 mmol, 1.00 equiv.), and iron powder (689 mg, 12.3 mmol, 5.00 equiv.) in ethanol (10.0 mL) and water (5.00 mL) was stirred at 90°C for 10 hours. The reaction was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column chromatography and lyophilized to give 3-chloro-4-methyl-5-((4-methylpiperazin-1-yl)methyl)aniline (0.60 g, 2.36 mmol, 96% yield) as a gray solid.

Step 3: To a solution of 3-chloro-4-methyl-5-((4-methylpiperazin-1-yl)methyl)aniline (0.30 g, 1.18 mmol, 1.00 equiv.) and potassium carbonate (326 mg, 2.36 mmol, 2.00 equiv.) in acetone (5.00 mL) was added dropwise phenyl chloroformate (0.22 mL, 1.77 mmol, 1.50 equiv.) at 0°C. The reaction was stirred at 25°C for 3 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column chromatography and lyophilized to give phenyl (3-chloro-4-methyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)carbamate (0.25 g, 669 μmol, 57% yield) as a gray solid.

Compound 125: Prepared using General Procedure A with Variant iii) in 58% yield from Compound VI using phenyl (3-chloro-5-(2-methoxyethoxy)-4-methylphenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (br s, 1H), 8.80 (s, 1H), 7.66 (s, 1H), 7.57 (s, 2H), 7.19 (d, J = 1.7 Hz, 1H), 7.01 (d, J = 1.6 Hz, 1H), 6.88 (br t, J = 6.0 Hz, 1H), 5.12 (dd, J = 5.0, 13.3 Hz, 1H), 4.50 - 4.26 (m, 4H), 4.12 - 3.98 (m, 2H), 3.75 - 3.61 (m, 2H), 3.33 (br s, 3H), 3.01 - 2.83 (m, 1H), 2.68 - 2.59 (m, 1H), 2.44 - 2.38 (m, 1H), 2.11 (s, 3H), 2.06 - 1.96 (m, 1H). MS (ESI) m/z 515.1 [M+H] ⁺

Scheme for the preparation of phenyl(3-chloro-5-(2-methoxyethoxy)-4-methylphenyl)carbamate.

Step 1: A mixture of methyl 3-chloro-5-hydroxy-4-methylbenzoate (1.00 g, 4.98 mmol, 1.00 equiv.), 1-bromo-2-methoxyethane (0.94 mL, 9.97 mmol, 2.00 equiv.), and potassium carbonate (2.76 g, 19.9 mmol, 4.00 equiv.) in acetonitrile (20.0 mL) was stirred at 85°C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1 to 5/1) to give methyl 3-chloro-5-(2-methoxyethoxy)-4-methylbenzoate (1.10 g, 4.25 mmol, 85% yield) as a yellow solid.

Step 2: A mixture of methyl 3-chloro-5-(2-methoxyethoxy)-4-methylbenzoate (1.00 g, 3.87 mmol, 1.00 equiv.) and sodium hydroxide (309 mg, 7.73 mmol, 2.00 equiv.) in methanol (10.0 mL) and water (10.0 mL) was stirred at 70°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (10.0 mL) and adjusted to pH 3 with hydrogen chloride (1N). The mixture was extracted with ethyl acetate (3 x 10.0 mL). The combined organic layers were washed with brine (3 x 10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-chloro-5-(2-methoxyethoxy)-4-methylbenzoic acid (850 mg, 3.47 mmol, 89% yield) as a yellow solid.

Step 3: A solution of 3-chloro-5-(2-methoxyethoxy)-4-methyl-benzoic acid (650 mg, 2.66 mmol, 1.00 equiv.), diphenylphosphoryl azide (0.86 mL, 3.98 mmol, 1.50 equiv.), and triethylamine (0.74 mL, 5.31 mmol, 2.00 equiv.) in 2-methylpropan-2-ol (10.0 mL) was stirred at 100°C for 12 hours. The mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layers were washed with brine (3 x 10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 to 3/1) to obtain tert-butyl (3-chloro-5-(2-methoxyethoxy)-4-methylphenyl)carbamate (700 mg, 2.22 mmol, 83% yield) as a yellow oil.

Step 4: A solution of tert-butyl (3-chloro-5-(2-methoxyethoxy)-4-methylphenyl)carbamate (650 mg, 2.06 mmol, 1.00 equivalents) in hydrogen chloride/ethyl acetate (2.00 mL) was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to give 3-chloro-5-(2-methoxyethoxy)-4-methyl-aniline hydrochloride (500 mg, 1.98 mmol, 96% yield, hydrochloride salt) as a yellow solid.

Step 5: To a solution of 3-chloro-5-(2-methoxyethoxy)-4-methyl-aniline hydrochloride (430 mg, 1.99 mmol, 1.00 equivalents, hydrochloride salt) and triethylamine (555 μL, 3.99 mmol, 2.00 equivalents) in dichloromethane (10.0 mL) was added dropwise phenyl chloroformate (0.30 mL, 2.39 mmol, 1.20 equivalents) at 0°C. The reaction was stirred at 25°C for 0.5 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 to 1/1) to give phenyl (3-chloro-5-(2-methoxyethoxy)-4-methylphenyl)carbamate (300 mg, 893 μmol, 44% yield) as a yellow solid.

Compound 126: Prepared using General Procedure A with Variant iii) in 31% yield from Compound VI using phenyl (3-chloro-4-methyl-5-((4-morpholinopiperidin-1-yl)methyl)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 8.83 (s, 1H), 8.18 (s, 1H), 7.69 - 7.61 (m, 2H), 7.56 (d, J = 0.8 Hz, 2H), 7.12 (d, J = 2.0 Hz, 1H), 6.88 - 6.80 (m, 1H), 5.12 (dd, J = 5.2, 13.2 Hz, 1H), 4.46 - 4.25 (m, 4H), 3.64 - 3.48 (m, 4H), 3.37 (s, 2H), 2.98 - 2.77 (m, 3H), 2.62 - 2.57 (m, 1H), 2.46 (br d, J = 3.8 Hz, 4H), 2.40 (br dd, J = 4.4, 13.2 Hz, 1H), 2.24 (s, 3H), 2.15 (br t, J = 10.8 Hz, 1H), 2.05 - 1.89 (m, 3H), 1.74 (br d, J = 11.2 Hz, 2H), 1.45 - 1.29 (m, 2H). MS (ESI) m/z 623.1 [M+H] ⁺

Scheme for the preparation of phenyl(3-chloro-4-methyl-5-((4-morpholinopiperidin-1-yl)methyl)phenyl)carbamate.

Step 1: To a solution of (3-chloro-2-methyl-5-nitrophenyl)methanol (1.00 g, 4.96 mmol, 1.00 equiv.) in dichloromethane (15.0 mL) was added thionyl chloride (2.95 g, 24.8 mmol, 1.80 mL, 5.00 equiv.) at 0°C. The reaction was then stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to give 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene (1.10 g, 4.96 mmol, crude) as a yellow oil, which was used directly in the next step.

Step 2: To a solution of 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene (1.10 g, 5.00 mmol, 1.00 equiv.) and triethylamine (1.26 g, 12.5 mmol, 1.74 mL, 2.50 equiv.) in acetonitrile (10.0 mL) was added 4-(piperidin-4-yl)morpholine (1.06 g, 6.25 mmol, 1.25 equiv.). The reaction was stirred at 25°C for 10 hours. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase column chromatography and lyophilized to provide 4-(1-(3-chloro-2-methyl-5-nitrobenzyl)piperidin-4-yl)morpholine (1.00 g, 2.83 mmol, 57% yield) as a yellow solid.

Step 3: A mixture of 4-(1-(3-chloro-2-methyl-5-nitrobenzyl)piperidin-4-yl)morpholine (1.00 g, 2.83 mmol, 1.00 equiv.), ammonium chloride (151 mg, 2.83 mmol, 1.00 equiv.), and iron powder (789 mg, 14.1 mmol, 5.00 equiv.) in ethanol (20.0 mL) and water (10.0 mL) was stirred at 90°C for 10 hours. The mixture was filtered and concentrated under reduced pressure to give 3-chloro-4-methyl-5-((4-morpholinopiperidin-1-yl)methyl)aniline (0.950 g, 2.83 mmol, crude) as a yellow oil, which was used directly in the next step.

Step 4: To a solution of 3-chloro-4-methyl-5-((4-morpholinopiperidin-1-yl)methyl)aniline (0.92 g, 2.84 mmol, 1.00 equiv.) and potassium carbonate (785 mg, 5.68 mmol, 2.00 equiv.) in acetone (10.0 mL) was added phenyl chloroformate (0.53 mL, 4.26 mmol, 1.50 equiv.) dropwise. The reaction was stirred at 25°C for 10 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (3 x 35.0 mL). The combined organic layers were washed with brine (15.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give phenyl (3-chloro-4-methyl-5-((4-morpholinopiperidin-1-yl)methyl)phenyl)carbamate (1.50 g, 2.84 mmol, crude) as a yellow oil, which was used directly in the next step.

Compound 127: Prepared using General Procedure A with Variant iii) in 34% yield from Compound VI using phenyl (3-chloro-4-methyl-5-(2-morpholinoethoxy)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.0 (s, 1H), 10.8 - 10.6 (m, 1H), 9.03 (s, 1H), 7.66 (s, 1H), 7.57 (s, 2H), 7.20 - 7.11 (m, 2H), 6.99 (br t, J = 6.0 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.49 - 4.22 (m, 6H), 3.99 (br d, J = 12.5 Hz, 2H), 3.76 (br t, J = 11.9 Hz, 2H), 3.60 (br d, J = 1.1 Hz, 2H), 3.50 (br d, J = 12.6 Hz, 2H), 3.27 - 3.15 (m, 2H), 3.00 - 2.85 (m, 1H), 2.71 - 2.58 (m, 1H), 2.40 - 2.30 (m, 1H), 2.16 (s, 3H), 2.03 - 1.94 (m, 1H). MS (ESI) m/z 570.3 [M+H] ⁺

Scheme for the preparation of phenyl(3-chloro-4-methyl-5-(2-morpholinoethoxy)phenyl)carbamate.

Step 1: To a solution of methyl 3-chloro-5-hydroxy-4-methylbenzoate (600 mg, 3.00 mmol, 1.00 equiv.) in acetonitrile (6.00 mL), potassium iodide (49.7 mg, 0.30 mmol, 0.10 equiv.), potassium carbonate (1.65 g, 12.0 mmol, 4.00 equiv.), and 4-(2-chloroethyl)morpholine hydrochloride (1.11 g, 5.98 mmol, 2.00 equiv., hydrochloric acid) were added. The reaction was stirred at 80°C for 12 hours. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (dichloromethane/methanol = 1/0 to 10/1) to give methyl 3-chloro-4-methyl-5-(2-morpholinoethoxy)benzoate (820 mg, 2.61 mmol, 87% yield) as a white solid.

Step 2: To a solution of methyl 3-chloro-4-methyl-5-(2-morpholinoethoxy)benzoate (770 mg, 2.45 mmol, 1.00 equiv.) in tetrahydrofuran (3.00 mL) and water (1.00 mL), lithium hydroxide monohydrate (309 mg, 7.36 mmol, 3.00 equiv.) was added. The reaction was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column chromatography and lyophilized to give a residue. Water (20 mL) and hydrochloric acid (0.20 mL) were added to the residue, which was then lyophilized to give 3-chloro-4-methyl-5-(2-morpholinoethoxy)benzoic acid (650 mg, 2.17 mmol, 88% yield) as a white solid.

Step 3: To a solution of 3-chloro-4-methyl-5-(2-morpholinoethoxy)benzoic acid (600 mg, 2.00 mmol, 1.00 equiv.) in toluene (6.00 mL), triethylamine (446 mg, 4.40 mmol, 2.20 equiv.) and diphenylphosphoryl azide (606 mg, 2.20 mmol, 1.10 equiv.) were added. The reaction was stirred at 20°C for 10 minutes, and then phenol (942 mg, 10.0 mmol, 5.00 equiv.) was added. The reaction was stirred at 100°C for 30 minutes. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 0/1) to obtain phenyl (3-chloro-4-methyl-5-(2-morpholinoethoxy)phenyl)carbamate (80.0 mg, 205 μmol, 10% yield) as a yellow oil.

Compound 128: Prepared using General Procedure A with Variant iii) in 46% yield from Compound VI using phenyl(1-methyl-1H-pyrrol-3-yl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (s, 1H), 7.99 (s, 1H), 7.63 (s, 1H), 7.53 (s, 2H), 6.71 (t, J = 2.0 Hz, 1H), 6.46 (t, J = 2.5 Hz, 1H), 6.42 (br t, J = 5.9 Hz, 1H), 5.80 - 5.75 (m, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.47 - 4.25 (m, 4H), 3.51 (s, 3H), 2.97 - 2.84 (m, 1H), 2.63 - 2.55 (m, 1H), 2.39 (dd, J = 4.4, 13.1 Hz, 1H), 2.03 - 1.95 (m, 1H). MS (ESI) m/z 396.1 [M+H] ⁺

Scheme for the preparation of phenyl(1-methyl-1H-pyrrol-3-yl)carbamate.

Step 1: To a solution of 1-methyl-1H-pyrrole-3-carboxylic acid (700 mg, 5.59 mmol, 1.00 equiv.) in toluene (7.00 mL), diphenylphosphoryl azide (1.33 mL, 6.15 mmol, 1.10 equiv.) and triethylamine (0.86 mL, 6.15 mmol, 1.10 equiv.) were added. The reaction was stirred at 20°C for 10 minutes, and then phenol (2.46 mL, 28.0 mmol, 5.00 equiv.) was added, and the reaction was stirred at 100°C for 30 minutes. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 5/1) to give phenyl(1-methyl-1H-pyrrol-3-yl)carbamate (350 mg, 1.62 mmol, 29% yield) as a pink solid.

Compound 129: Prepared using General Procedure A with Variant iii) in 46% yield from Compound VI using phenyl (3-chloro-5-(dimethylamino)-4-methylphenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (br s, 1H), 8.78 (br s, 1H), 7.65 (s, 1H), 7.56 (s, 2H), 7.32 (d, J = 2.0 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.82 (br d, J = 2.9 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.47 - 4.27 (m, 4H), 2.97 - 2.85 (m, 1H), 2.64 - 2.60 (m, 1H), 2.59 (s, 6H), 2.39 (dd, J = 4.4, 13.0 Hz, 1H), 2.19 (s, 3H), 2.04 - 1.96 (m, 1H). MS (ESI) m/z 484.2 [M+H] ⁺

Scheme for the preparation of phenyl(3-chloro-5-(dimethylamino)-4-methylphenyl)carbamate.

Step 1: To a solution of methyl 3-chloro-5-iodo-4-methylbenzoate (9.00 g, 29.0 mmol, 1.00 equiv.) in toluene (180 mL) was added 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (5.41 g, 8.70 mmol, 0.30 equiv.), diphenylmethanimine (5.84 mL, 34.8 mmol, 1.20 equiv.), sodium tert-butoxide (3.90 g, 40.6 mmol, 1.40 equiv.), and tris(dibenzylideneacetone)dipalladium (2.65 g, 2.90 mmol, 0.10 equiv.). The reaction was stirred under nitrogen at 80°C for 12 hours. The mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 10/1) to obtain methyl 3-chloro-5-((diphenylmethylene)amino)-4-methylbenzoate (6.50 g, 17.9 mmol, 62% yield) as a yellow oil.

Step 2: To a solution of methyl 3-chloro-5-((diphenylmethylene)amino)-4-methylbenzoate (6.50 g, 17.9 mmol, 1.00 equiv.) in tetrahydrofuran (65.0 mL), hydrochloric acid (1.00 M, 17.9 mL, 1.00 equiv.) was added. The reaction was stirred at 20°C for 2 hours. Water (60.0 mL) was added, followed by saturated sodium bicarbonate until pH = 8. The mixture was extracted with ethyl acetate (3 x 60.0 mL). The organic phase was collected, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 5/1) to give methyl 3-amino-5-chloro-4-methylbenzoate (2.86 g, 14.3 mmol, 80% yield) as a yellow solid.

Step 3: To a solution of methyl 3-amino-5-chloro-4-methylbenzoate (2.86 g, 14.3 mmol, 1.00 equiv.) in dimethylformamide (30.0 mL) was added iodomethane (2.68 mL, 43.0 mmol, 3.00 equiv.) and potassium carbonate (7.92 g, 57.3 mmol, 4.00 equiv.). The reaction was stirred at 80°C for 5 hours. Water (40.0 mL) was added, and the mixture was extracted with ethyl acetate (3 x 50.0 mL). The organic layer was collected, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 5/1) to give methyl 3-chloro-5-(dimethylamino)-4-methylbenzoate (2.45 g, 10.8 mmol, 75% yield) as a clear oil.

Step 4: To a solution of methyl 3-chloro-5-(dimethylamino)-4-methylbenzoate (2.30 g, 10.1 mmol, 1.00 equiv.) in tetrahydrofuran (18.0 mL) and water (6.00 mL), lithium hydroxide (484 mg, 20.2 mmol, 2.00 equiv.) was added. The reaction was stirred at 20°C for 12 hours. Water (20.0 mL) was added, and the mixture was extracted with ethyl acetate (2 x 40.0 mL). 1M hydrochloric acid was added to the aqueous layer until pH = 7, and it was extracted with ethyl acetate (2 x 40.0 mL). The organic layer was collected, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3-chloro-5-(dimethylamino)-4-methylbenzoic acid (1.90 g, 8.89 mmol, 88% yield) as a white solid.

Step 5: To a solution of 3-chloro-5-(dimethylamino)-4-methylbenzoic acid (700 mg, 3.28 mmol, 1.00 equiv.) and triethylamine (0.50 mL, 3.60 mmol, 1.10 equiv.) in toluene (7.00 mL) was added diphenylphosphoryl azide (0.78 mL, 3.60 mmol, 1.10 equiv.). The reaction was stirred at 20°C for 10 minutes, and then phenol (1.44 mL, 16.4 mmol, 5.00 equiv.) was added. The reaction was stirred at 100°C for 30 minutes. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 5/1) to give phenyl (3-chloro-5-(dimethylamino)-4-methylphenyl)carbamate (1 g, crude) as a clear oil, which was used directly in the next reaction.

Compound 130: Prepared using General Procedure A with Variant iii) in 50% yield from Compound VI using phenyl N-[3-[(1-methyl-4-piperidyl)oxy]phenyl]carbamate.

¹ H NMR (DMSO-d ₆ ) δ = 10.96 (s, 1H), 8.61 (br s, 1H), 8.16 (s, 1H), 7.65 (s, 1H), 7.55 (s, 2H), 7.17 (s, 1H), 7.12 - 7.05 (m, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.75 (br s, 1H), 6.48 (dd, J = 8.2, 2.2 Hz, 1H), 5.11 (dd, J = 13.3, 5.2 Hz, 1H), 4.46 - 4.37 (m, 3H), 4.30 (br d, J = 17.0 Hz, 2H), 2.96 - 2.85 (m, 1H), 2.67 - 2.55 (m, 3H), 2.39 (br dd, J = 13.1, 4.5 Hz, 1H), 2.30 - 2.23 (m, 2H), 2.27 - 2.23 (m, 2H), 2.21 (br s, 3H), 2.03 - 1.95 (m, 1H), 1.90 (br s, 2H), 1.63 (br d, J = 8.2 Hz, 2H). MS (ESI) m/z 506.4 [M+H] ⁺

Scheme for the preparation of phenyl N-[3-[(1-methyl-4-piperidyl)oxy]phenyl]carbamate.

Step 1: A solution of tert-butyl 4-(3-nitrophenoxy)piperidine-1-carboxylate (800 mg, 2.48 mmol, 1.00 equivalents) in hydrochloric acid/ethyl acetate (10.0 mL) was stirred at 25°C for 0.5 hours. The mixture was concentrated under reduced pressure to give 4-(3-nitrophenoxy)piperidine (630 mg, crude) as a white solid, which was used directly in the next reaction.

Step 2: To a solution of 4-(3-nitrophenoxy)piperidine (500 mg, 2.25 mmol, 1.00 equiv.) in methanol (20.0 mL) was added formaldehyde (37% purity, 0.50 mL, 6.75 mmol, 3.00 equiv.) and sodium cyanoborohydride (424 mg, 6.75 mmol, 3.00 equiv.). The reaction was stirred at 25°C for 4 hours. The mixture was concentrated under reduced pressure to give a residue. Water (10.0 mL) was added, and the solution was extracted with dichloromethane (3 x 20.0 mL). The combined organic layers were washed with brine (3 x 10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (dichloromethane/methanol = 10/1) to obtain 1-methyl-4-(3-nitrophenoxy)piperidine (330 mg, 1.40 mmol, 62% yield) as a yellow oil.

Step 3: To a solution of 1-methyl-4-(3-nitrophenoxy)piperidine (320 mg, 1.35 mmol, 1.00 equiv.) in tetrahydrofuran (5.00 mL) was added 10% wt. Pd/C on C (100 mg, 1.00 equiv.). The reaction was stirred under a hydrogen atmosphere (15 psi) at 20°C for 4 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 3-[(1-methyl-4-piperidyl)oxy]aniline (270 mg, 1.31 mmol, 97% yield) as a yellow solid.

Step 4: To a solution of 3-[(1-methyl-4-piperidyl)oxy]aniline (270 mg, 1.31 mmol, 1.00 equiv.) in dichloromethane (10.0 mL) was added pyridine (0.32 mL, 3.93 mmol, 3.00 equiv.) at 0°C, followed by the addition of phenyl chloroformate (0.18 mL, 1.44 mmol, 1.10 equiv.). The reaction was stirred at 20°C for 6 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (15.0 mL) and extracted with dichloromethane (3 x 20.0 mL). The combined organic layers were washed with brine (3 x 10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (dichloromethane/methanol = 10/1) to obtain phenyl N-[3-[(1-methyl-4-piperidyl)oxy]phenyl]carbamate (230 mg, 704 μmol, 54% yield) as a yellow solid.

Compound 131: Prepared using General Procedure A with Variant iii) in 50% yield from Compound VI using phenyl(4-(2-hydroxypropan-2-yl)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (br s, 1H), 8.56 (s, 1H), 7.67 (s, 1H), 7.57 (s, 2H), 7.31 (s, 4H), 6.73 (br t, J = 6.0 Hz, 1H), 5.12 (dd, J = 5.0, 13.2 Hz, 1H), 4.85 (s, 1H), 4.50 - 4.23 (m, 4H), 3.02 - 2.84 (m, 1H), 2.66 - 2.56 (m, 1H), 2.44 - 2.34 (m, 1H), 2.05 - 1.96 (m, 1H), 1.39 (s, 6H). MS (ESI) m/z 449.5 [MH] ^-

Scheme for the preparation of phenyl(4-(2-hydroxypropan-2-yl)phenyl)carbamate.

Step 1: To a mixture of 1-(4-nitrophenyl)ethanone (2.00 g, 12.1 mmol, 1.00 equiv.) in ethanol (18.0 mL) and water (9.00 mL), ammonium chloride (648 mg, 12.1 mmol, 1.00 equiv.) and iron powder (3.38 g, 60.6 mmol, 5.00 equiv.) were added. The reaction was stirred at 90°C for 10 hours. The mixture was filtered, and the filtrate was extracted with ethyl acetate (3 x 30.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 1-(4-aminophenyl)ethanone (1.60 g, 11.8 mmol, 98% yield) as a yellow solid.

Step 2: To a solution of 1-(4-aminophenyl)ethanone (1.60 g, 11.8 mmol, 1.00 equiv.) in tetrahydrofuran (20.0 mL) at 0°C, methylmagnesium bromide (3.00 M, 11.8 mL, 3.00 equiv.) was added dropwise. The reaction was then stirred at 25°C for 10 hours. The mixture was quenched by adding saturated ammonium chloride (15.0 mL), diluted with water (10.0 mL), and extracted with ethyl acetate (3 x 55.0 mL). The combined organic layers were washed with brine (25.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC to give 2-(4-aminophenyl)propan-2-ol (0.45 g, 2.98 mmol, 25% yield) as a yellow solid.

Step 3: To a solution of 2-(4-aminophenyl)propan-2-ol (0.45 g, 2.98 mmol, 1.00 equiv.) and 2,6-dimethylpyridine (0.38 mL, 3.27 mmol, 1.10 equiv.) in tetrahydrofuran (3.00 mL) and trichloromethane (3.00 mL) at 0°C, phenyl chloroformate (0.37 mL, 2.98 mmol, 1.00 equiv.) was added. The reaction was stirred at 0°C for 1 hour. The mixture was diluted with water (10.0 mL) and extracted with dichloromethane (3 x 35.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide phenyl(4-(2-hydroxypropan-2-yl)phenyl)carbamate (0.80 g, 2.98 mmol, crude) as a white solid. It was used directly in the next reaction.

Compound 132: Prepared using General Procedure A with Variant iii) in 46% yield from Compound VI using phenyl(3-((1,3-dioxan-5-yl)methyl)-5-chloro-4-methylphenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.77 (s, 1H), 7.66 (s, 1H), 7.57 (s, 3H), 7.02 (d, J = 2.0 Hz, 1H), 6.86 (t, J = 6.0 Hz, 1H), 5.12 (dd, J = 5.2, 13.2 Hz, 1H), 4.83 (d, J = 6.0 Hz, 1H), 4.69 (d, J = 6.0 Hz, 1H), 4.49 - 4.26 (m, 4H), 3.86 (dd, J = 3.8, 11.2 Hz, 2H), 3.51 (dd, J = 7.6, 11.2 Hz, 2H), 2.99 - 2.83 (m, 1H), 2.66 - 2.54 (m, 3H), 2.40 (dq, J = 4.4, 13.2 Hz, 1H), 2.22 (s, 3H), 2.05 - 1.97 (m, 1H), 1.93 (dt, J = 3.6, 7.4 Hz, 1H). MS (ESI) m/z 541.3 [M+H] ⁺

Scheme for the preparation of phenyl(3-((1,3-dioxan-5-yl)methyl)-5-chloro-4-methylphenyl)carbamate.

Step 1: To a solution of 3-chloro-2-methylbenzoic acid (41.0 g, 240 mmol, 1.00 equiv.) in sulfuric acid (200 mL) was added nitric acid (12.3 mL, 264 mmol, 1.10 equiv.) dropwise at -10°C. The reaction was stirred at -10°C for 1 hour. The mixture was poured into stirred ice water (200 mL). The resulting precipitate was collected by filtration and washed with water to give 3-chloro-2-methyl-5-nitrobenzoic acid (52.0 g, 241 mmol, crude) as a white solid, which was used directly in the next step.

Step 2: To a solution of 3-chloro-2-methyl-5-nitrobenzoic acid (52.0 g, 67.5 mmol, 1.00 equiv.) in tetrahydrofuran (400 mL) was added borane dimethyl sulfide complex (10.0 M, 13.5 mL, 2.00 equiv.) at 0°C. The reaction was stirred at 25°C for 10 hours. Water (25.0 mL) was added at 0°C, and the pH was adjusted to 10.0 by adding 15% sodium hydroxide solution. The mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to give (3-chloro-2-methyl-5-nitrophenyl)methanol (3.00 g, 14.9 mmol, 22% yield) as a yellow solid.

Step 3: To a solution of (3-chloro-2-methyl-5-nitrophenyl)methanol (1.10 g, 5.46 mmol, 1.00 equiv.) in dichloromethane (10.0 mL) was added thionyl chloride (3.25 g, 27.3 mmol, 1.98 mL, 5.00 equiv.) at 0°C. The reaction was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (10.0 mL) and extracted with ethyl acetate (3 x 35.0 mL). The combined organic layers were washed with brine (2 x 10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene (1.30 g, 5.91 mmol, crude) as a yellow oil, which was used directly in the next step.

Step 4: To a solution of 60% pure sodium hydride (473 mg, 11.8 mmol, 2.00 equiv.) in tetrahydrofuran (15.0 mL) at 0°C, diethyl malonate (1.79 mL, 11.8 mmol, 2.00 equiv.) was slowly added. After 1 hour, 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene (1.30 g, 5.91 mmol, 1.00 equiv.) was added, and the reaction was stirred at 25°C for 10 hours. Water (10.0 mL) was added, and the mixture was extracted with ethyl acetate (3 x 35.0 mL). The combined organic layers were washed with brine (2 x 10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain diethyl 2-(3-chloro-2-methyl-5-nitrobenzyl)malonate (2.00 g, 5.82 mmol, 98% yield) as a yellow oil.

Step 5: To a solution of diethyl 2-(3-chloro-2-methyl-5-nitrobenzyl)malonate (2.00 g, 5.82 mmol, 1.00 equiv.) in tetrahydrofuran (16.0 mL) at 0°C, sodium borohydride (1.10 g, 29.1 mmol, 5.00 equiv.) was added in small portions. Methanol (4.00 mL) was added, and the reaction was stirred at 25°C for 10 hours. Water (10.0 mL) was added, and the organic solvent was removed under reduced pressure. The aqueous layer was adjusted to pH 2.00 by adding 1N hydrochloric acid, and it was extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were washed with brine (15.0 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 2-(3-chloro-2-methyl-5-nitrobenzyl)propane-1,3-diol (1.40 g, 5.39 mmol, 93% yield) as a yellow solid.

Step 6: To a solution of 2-(3-chloro-2-methyl-5-nitrobenzyl)propane-1,3-diol (1.40 g, 5.39 mmol, 1.00 equiv.) in dichloromethane (10.0 mL) was added dimethoxymethane (715 μL, 8.09 mmol, 1.50 equiv.) and boron trifluoride diethyl etherate (1 mL, 8.09 mmol, 1.50 equiv.). The reaction was stirred at 25°C for 1.5 hours. The mixture was diluted with water (10.0 mL) and extracted with dichloromethane (3 x 35.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain 5-(3-chloro-2-methyl-5-nitrobenzyl)-1,3-dioxane (1.00 g, 3.68 mmol, 68% yield) as a white solid.

Step 7: A mixture of 5-(3-chloro-2-methyl-5-nitrobenzyl)-1,3-dioxane (1.00 g, 3.68 mmol, 1.00 equiv.), ammonium chloride (197 mg, 3.68 mmol, 1.00 equiv.), and iron powder (1.03 g, 18.4 mmol, 5.00 equiv.) in ethanol (15.0 mL) and water (7.00 mL) was stirred at 90°C for 10 hours. The mixture was filtered and concentrated under reduced pressure to give a residue. Water (10.0 mL) was added, and the mixture was extracted with ethyl acetate (3 x 35.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3-((1,3-dioxan-5-yl)methyl)-5-chloro-4-methylaniline (0.88 g, 3.64 mmol, 99% yield) as a yellow solid.

Step 8: To a solution of 3-((1,3-dioxan-5-yl)methyl)-5-chloro-4-methylaniline (0.20 g, 827 μmol, 1.00 equiv.) and potassium carbonate (229 mg, 1.65 mmol, 2.00 equiv.) in acetone (5.00 mL) was added phenyl chloroformate (124 μL, 993 μmol, 1.20 equiv.). The reaction was stirred at 25°C for 10 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (3 x 30.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give phenyl(3-((1,3-dioxan-5-yl)methyl)-5-chloro-4-methylphenyl)carbamate (0.30 g, 829 μmol, crude) as a yellow solid. It was used directly in the next step.

Compound 133: Prepared using General Procedure A with Variant iii) in 65% yield from Compound VI using phenyl (3-chloro-5-((4-(dimethylamino)piperidin-1-yl)methyl)-4-methylphenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.98 (s, 1H), 8.24 (s, 2H), 7.69 - 7.61 (m, 2H), 7.57 (d, J = 0.8 Hz, 2H), 7.14 (d, J = 2.0 Hz, 1H), 7.08 - 6.96 (m, 1H), 5.12 (dd, J = 5.2, 13.2 Hz, 1H), 4.47 - 4.28 (m, 4H), 3.37 (s, 2H), 2.99 - 2.57 (m, 3H), 2.47 - 2.39 (m, 2H), 2.37 (s, 6H), 2.34 - 2.26 (m, 1H), 2.25 (s, 3H), 2.05 - 1.92 (m, 3H), 1.80 (br d, J = 11.4 Hz, 2H), 1.44 (br dd, J = 3.2, 11.8 Hz, 2H). MS (ESI) m/z 581.4 [M+H] ⁺

Scheme for the preparation of phenyl(3-chloro-5-((4-(dimethylamino)piperidin-1-yl)methyl)-4-methylphenyl)carbamate.

Step 1: To a solution of (3-chloro-2-methyl-5-nitrophenyl)methanol (0.80 g, 3.97 mmol, 1.00 equiv.) in dichloromethane (10.0 mL) was added thionyl chloride (1.44 mL, 19.8 mmol, 5.00 equiv.) at 0°C. The reaction was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to give 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene (0.90 g, 4.09 mmol, crude) as a yellow oil, which was used directly in the next step.

Step 2: To a solution of 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene (0.90 g, 4.09 mmol, 1.00 equiv.) and triethylamine (1.42 mL, 10.2 mmol, 2.50 equiv.) in acetonitrile (10.0 mL) was added N,N-dimethylpiperidin-4-amine (655 mg, 5.11 mmol, 1.25 equiv.). The reaction was stirred at 25°C for 10 hours. The mixture was filtered and concentrated under reduced pressure to afford 1-(3-chloro-2-methyl-5-nitrobenzyl)-N,N-dimethylpiperidin-4-amine (1.3 g, 4.09 mmol, crude) as a gray solid, which was used directly in the next step.

Step 3: A mixture of 1-(3-chloro-2-methyl-5-nitrobenzyl)-N,N-dimethylpiperidin-4-amine (1.30 g, 4.17 mmol, 1.00 equiv.), ammonium chloride (223 mg, 4.17 mmol, 1.00 equiv.), and iron powder (1.16 g, 20.9 mmol, 5.00 equiv.) in ethanol (20.0 mL) and water (10.0 mL) was stirred at 90°C for 10 hours. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column chromatography and lyophilized to give 1-(5-amino-3-chloro-2-methylbenzyl)-N,N-dimethylpiperidin-4-amine (0.6 g, 4.17 mmol, crude) as a brown solid, which was used directly in the next step.

Step 4: To a solution of 1-(5-amino-3-chloro-2-methylbenzyl)-N,N-dimethylpiperidin-4-amine (0.60 g, 2.13 mmol, 1.00 equiv.) and potassium carbonate (588 mg, 4.26 mmol, 2.00 equiv.) in acetone (10.0 mL) was added phenyl chloroformate (400 mg, 2.55 mmol, 320 μL, 1.20 equiv.). The reaction was stirred at 25°C for 1 hour. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC to give phenyl (3-chloro-5-((4-(dimethylamino)piperidin-1-yl)methyl)-4-methylphenyl)carbamate (50.0 mg, 124 μmol, 5.84% yield) as a yellow solid.

Compound 134: Prepared using General Procedure A with Variant iii) in 25% yield from Compound VI using phenyl (3-chloro-5-(2-(dimethylamino)ethoxy)-4-methylphenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.0 (s, 1H), 10.6 (br s, 1H), 9.28 (s, 1H), 7.65 (s, 1H), 7.57 (s, 2H), 7.25 - 7.07 (m, 3H), 5.12 (dd, J = 5.1, 13.2 Hz, 1H), 4.49 - 4.37 (m, 3H), 4.35 - 4.26 (m, 3H), 3.57 - 3.49 (m, 2H), 2.97 - 2.88 (m, 1H), 2.86 (s, 3H), 2.85 (s, 3H), 2.60 (br d, J = 16.7 Hz, 1H), 2.46 - 2.33 (m, 1H), 2.16 (s, 3H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 528.4 [M+H] ⁺

Scheme for the preparation of phenyl(3-chloro-5-(2-(dimethylamino)ethoxy)-4-methylphenyl)carbamate.

Step 1: To a solution of methyl 3-chloro-5-hydroxy-4-methylbenzoate (600 mg, 2.99 mmol, 1.00 equiv.) in acetonitrile (6.00 mL), potassium iodide (49.7 mg, 299 μmol, 0.10 equiv.), potassium carbonate (1.65 g, 12.0 mmol, 4.00 equiv.), and 2-chloro-N,N-dimethylethanamine (862 mg, 5.98 mmol, 2.00 equiv., hydrochloric acid) were added. The reaction was stirred at 80°C for 12 hours. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 1/0 to 10/1) to give methyl 3-chloro-5-(2-(dimethylamino)ethoxy)-4-methylbenzoate (550 mg, 2.02 mmol, 68% yield) as a yellow oil.

Step 2: To a solution of methyl 3-chloro-5-(2-(dimethylamino)ethoxy)-4-methylbenzoate (500 mg, 1.84 mmol, 1.00 equiv.) in tetrahydrofuran (1.50 mL) and water (0.50 mL), lithium hydroxide monohydrate (232 mg, 5.52 mmol, 3.00 equiv.) was added. The reaction was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column chromatography and lyophilized to give a solid. Water (20.0 mL) and then hydrochloric acid (0.20 mL) were added, and the mixture was lyophilized to give 3-chloro-5-(2-(dimethylamino)ethoxy)-4-methylbenzoic acid (350 mg, 1.36 mmol, 74% yield) as a white solid.

Step 3: To a solution of 3-chloro-5-(2-(dimethylamino)ethoxy)-4-methylbenzoic acid (300 mg, 1.16 mmol, 1.00 equiv.) in toluene (1.00 mL), triethylamine (259 mg, 2.56 mmol, 2.20 equiv.) and diphenylphosphoryl azide (352 mg, 1.28 mmol, 1.10 equiv.) were added. The reaction was stirred at 20°C for 10 minutes, and then phenol (548 mg, 5.82 mmol, 5.00 equiv.) was added. The reaction was stirred at 100°C for 30 minutes. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase column chromatography and lyophilized to provide the residue. The residue was purified by reverse-phase preparative HPLC and lyophilized to give phenyl (3-chloro-5-(2-(dimethylamino)ethoxy)-4-methylphenyl)carbamate (400 mg, 1.15 mmol, 99% yield) as a yellow solid.

Compound 135: Prepared using General Procedure A with Variant iii) in 13% yield from Compound VI using phenyl(3-(2-hydroxypropan-2-yl)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.00 (s, 1H), 8.65 (s, 1H), 7.67 (s, 1H), 7.57 (s, 2H), 7.46 (s, 1H), 7.33 (br d, J = 7.8 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.73 (t, J = 5.8 Hz, 1H), 5.12 (dd, J = 5.0, 13.2 Hz, 1H), 4.94 (s, 1H), 4.52 - 4.24 (m, 4H), 2.99 - 2.85 (m, 1H), 2.62 (br d, J = 2.4 Hz, 1H), 2.43 - 2.31 (m, 1H), 2.07 - 1.94 (m, 1H), 1.39 (s, 6H). MS (ESI) m/z 449.4 [MH] ^-

Scheme for the preparation of phenyl(3-(2-hydroxypropan-2-yl)phenyl)carbamate.

Step 1: A mixture of 1-(3-nitrophenyl)ethanone (2.00 g, 12.1 mmol, 1.00 equiv.), ammonium chloride (648 mg, 12.1 mmol, 1.00 equiv.), and iron powder (3.38 g, 60.6 mmol, 5.00 equiv.) in ethanol (20.0 mL) and water (10.0 mL) was stirred at 90°C for 10 hours. The mixture was filtered, and the filtrate was extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1-(3-aminophenyl)ethanone (1.60 g, 11.8 mmol, crude) as a white solid, which was used directly in the next reaction.

Step 2: To a solution of 1-(3-aminophenyl)ethanone (1.50 g, 11.1 mmol, 1.00 equiv.) in tetrahydrofuran (15.0 mL) at 0°C, methylmagnesium bromide (3.00 M, 11.1 mL, 3.00 equiv.) was added dropwise. The reaction was stirred at 25°C for 2 hours. The mixture was quenched by adding saturated ammonium chloride (8.00 mL), then diluted with water (5.00 mL) and extracted with ethyl acetate (3 x 30.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC to give 2-(3-aminophenyl)propan-2-ol (0.10 g, 661 μmol, 6% yield) as a white solid.

Step 3: To a solution of 2-(3-aminophenyl)propan-2-ol (0.10 g, 661 μmol, 1.00 equiv.) and 2,6-dimethylpyridine (84.7 μL, 727 μmol, 1.10 equiv.) in tetrahydrofuran (0.50 mL) and trichloromethane (0.50 mL) at 0°C, phenyl chloroformate (82.8 μL, 661 μmol, 1.00 equiv.) was slowly added. The reaction was stirred at 25°C for 2 hours. The mixture was diluted with water (5.00 mL) and extracted with dichloromethane (3 x 25.0 mL). The combined organic layers were washed with brine (8.00 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give phenyl (3-(2-hydroxypropan-2-yl)phenyl)carbamate (0.18 g, 663 μmol, crude) as a yellow oil, which was used directly in the next reaction.

Compound 136: Scheme for the preparation of compound 136.

Step 1: A mixture of 2-(dimethylamino)acetic acid (75.7 mg, 734 μmol, 1.50 equiv.), 4-dimethylaminopyridine (6.0 mg, 48.9 μmol, 0.10 equiv.), and N,N'-methanediylidene dicyclohexanamine (148 μL, 734 μmol, 1.50 equiv.) in dimethylformamide (5.00 mL) was stirred at 20°C for 30 minutes, followed by the addition of 1-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)-3-(3-hydroxyphenyl)urea (described in Example 110) (200 mg, 489 μmol, 1.00 equiv.). The reaction was stirred at 20°C for 12 hours, then at 40°C for 4 hours. The mixture was filtered, and the filtrate was purified by reverse-phase preparative HPLC to give compound 136 (70.2 mg, 125.8 μmol, 41% yield, hydrochloride salt) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1 H), 10.44 (br s, 1 H), 9.38 - 9.32 (m, 1 H), 7.66 (s, 1 H), 7.58 - 7.57 (m, 3 H), 7.32 - 7.28 (m, 1 H), 7.17 - 7.12 (m, 2 H), 6.75 - 6.73 (m, 1 H), 5.13 - 5.09 (m, 1 H), 4.49 - 4.33 (m, 6 H), 2.95 - 2.87 (m, 7 H), 2.62 - 2.58 (m, 1 H), 2.42 - 2.38 (m, 1 H), 2.02 - 2.00 (m, 1 H). MS (ESI) m/z 494.2 [M+H] ⁺

Compound 137: Prepared using General Procedure A with Variant iii) in 58% yield from Compound VI using phenyl (6-chloro-5-methylpyridin-2-yl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (br s, 1H), 9.44 (s, 1H), 7.69 - 7.64 (m, 2H), 7.62 - 7.59 (m, 1H), 7.57 (s, 2H), 7.48 (br t, J = 5.8 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.45 (m, 2H), 4.41 (s, 1H), 4.35 - 4.27 (m, 1H), 2.96 - 2.86 (m, 1H), 2.63 - 2.56 (m, 1H), 2.45 - 2.36 (m, 1H), 2.22 (s, 3H), 2.04 - 1.96 (m, 1H). MS (ESI) m/z 442.1 [M+H] ⁺

Scheme for the preparation of phenyl(6-chloro-5-methylpyridin-2-yl)carbamate.

Step 1: To a solution of 6-chloro-5-methyl-pyridin-2-amine (300 mg, 2.10 mmol, 1.00 equiv.) in dichloromethane (15.0 mL) at 0°C, pyridine (0.25 mL, 3.16 mmol, 1.50 equiv.) and phenyl chloroformate (0.26 mL, 2.10 mmol, 1.00 equiv.) were added. The reaction was stirred at 20°C for 2 hours. The mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (3 x 30.0 mL). The combined organic layers were washed with brine (3 x 20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give phenyl (6-chloro-5-methylpyridin-2-yl)carbamate (400 mg, 1.52 mmol, 72% yield) as a white solid.

Compound 138: Prepared using General Procedure A with Variant iii) in 55% yield from Compound VI using phenyl (3-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)-5-chloro-4-methylphenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.74 (s, 1H), 7.66 (s, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.56 (d, J = 1.0 Hz, 2H), 7.20 (d, J = 2.1 Hz, 1H), 6.76 (t, J = 6.1 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48 - 4.25 (m, 4H), 3.55 - 3.49 (m, 2H), 3.43 - 3.39 (m, 2H), 3.35 - 3.35 (m, 2H), 2.97 (br s, 2H), 2.95 - 2.84 (m, 1H), 2.63 - 2.56 (m, 1H), 2.45 - 2.34 (m, 1H), 2.28 (s, 3H), 2.04 - 1.90 (m, 3H), 1.82 - 1.68 (m, 2H). MS (ESI) m/z 566.2 [M+H] ⁺

Scheme for the preparation of phenyl(3-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)-5-chloro-4-methylphenyl)carbamate.

Step 1: To a solution of 1-(bromomethyl)-3-chloro-2-methyl-5-nitrobenzene (500 mg, 1.89 mmol, 1.00 equiv.) in acetonitrile (10.0 mL) was added 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (283 mg, 1.89 mmol, 1.00 equiv., hydrochloride salt), potassium carbonate (523 mg, 3.78 mmol, 2.00 equiv.), and potassium iodide (31.4 mg, 189 μmol, 0.10 equiv.). The reaction was stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL). The organic layer was washed with water (10.0 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 0/1, then dichloromethane/methanol = 10/1) to obtain 8-(3-chloro-2-methyl-5-nitrobenzyl)-3-oxa-8-azabicyclo[3.2.1]octane (390 mg, 1.31 mmol, 69% yield) as a brown solid.

Step 2: To a solution of 8-(3-chloro-2-methyl-5-nitrobenzyl)-3-oxa-8-azabicyclo[3.2.1]octane (390 mg, 1.31 mmol, 100 equiv.) and ammonium chloride (492 mg, 9.20 mmol, 7.00 equiv.) in methanol (5.00 mL) and water (5.00 mL), iron powder (514 mg, 9.20 mmol, 7.00 equiv.) was added. The reaction was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure to provide a residue. The residue was diluted with water (20 mL) and basified to pH 10 using sodium hydroxide. The mixture was extracted with ethyl acetate (50.0 mL). The organic layer was washed with water (20.0 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)-5-chloro-4-methylaniline (290 mg, 1.09 mmol, 82% yield) as a brown oil.

Step 3: To a solution of 3-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)-5-chloro-4-methylaniline (230 mg, 862 μmol, 1.00 equiv.) and potassium carbonate (119 mg, 862 μmol, 1.00 equiv.) in acetone (3.00 mL) was added phenyl chloroformate (0.11 mL, 862 μmol, 1.00 equiv.) dropwise. The reaction was stirred at 20°C for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 to 2/1) to obtain phenyl (3-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)-5-chloro-4-methylphenyl)carbamate (300 mg, 775 μmol, 89% yield) as a yellow oil.

Compound 139: Prepared using General Procedure A with Variant iii) in 19% yield from Compound VI using phenyl (3-(2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-5-chloro-4-methylphenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ + D ₂ O, T = 80°C) δ = 7.68 - 7.62 (m, 2H), 7.58 - 7.51 (m, 3H), 5.00 (dd, J = 5.3, 13.1 Hz, 1H), 4.67 (s, 1H), 4.50 - 4.32 (m, 7H), 4.26 - 4.12 (m, 1H), 3.73 (br d, J = 9.8 Hz, 1H), 3.37 - 3.28 (m, 2H), 2.94 - 2.77 (m, 1H), 2.71 - 2.59 (m, 1H), 2.46 - 2.34 (m, 2H), 2.34 (s, 3H), 2.12 - 2.01 (m, 2H). MS (ESI) m/z 552.3 [M+H] ⁺

Scheme for the preparation of phenyl(3-(2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-5-chloro-4-methylphenyl)carbamate.

Step 1: To a solution of 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (308 mg, 2.27 mmol, 1.00 equiv., hydrochloride salt) in acetonitrile (10.0 mL) was added 1-(bromomethyl)-3-chloro-2-methyl-5-nitrobenzene (600 mg, 2.27 mmol, 1.00 equiv.), potassium carbonate (627 mg, 4.54 mmol, 2.00 equiv.), and potassium iodide (37.6 mg, 227 μmol, 0.10 equiv.). The reaction was stirred at 80°C for 12 hours. The mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (3 x 40.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (2.00 mL) and filtered. The filter cake was dissolved in ethyl acetate (50.0 mL) and silica gel was added. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 5-(3-chloro-2-methyl-5-nitrobenzyl)-2-oxa-5-azabicyclo[2.2.1]heptane (550 mg, crude) as an orange solid.

Step 2: To a solution of 5-(3-chloro-2-methyl-5-nitrobenzyl)-2-oxa-5-azabicyclo[2.2.1]heptane (500 mg, 1.77 mmol, 1.00 equiv.) and ammonium chloride (662 mg, 12.4 mmol, 7.00 equiv.) in methanol (8.00 mL) and water (2.00 mL), iron powder (691 mg, 12.4 mmol, 7.00 equiv.) was added in small portions. The reaction was stirred at 70°C for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was diluted with water (60.0 mL) and extracted with ethyl acetate (3 x 40.0 mL). The combined organic layers were washed with brine (30.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1 to 0/1) to obtain 3-(2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-5-chloro-4-methylaniline (400 mg, crude) as a yellow solid, which was used directly in the next step.

Step 3: To a solution of 3-(2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-5-chloro-4-methylaniline (300 mg, 1.19 mmol, 1.00 equiv.) and phenyl chloroformate (0.15 mL, 1.19 mmol, 1.00 equiv.) in acetone (3.00 mL) was added potassium carbonate (492 mg, 3.56 mmol, 3.00 equiv.) in small portions. The reaction was stirred at 15°C for 2 hours. Water (30.0 mL) was added, and the mixture was extracted with ethyl acetate (3 x 30.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1 to 2/1) to obtain phenyl (3-(2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-5-chloro-4-methylphenyl)carbamate (250 mg, 671 μmol, 56% yield) as a yellow solid.

Compound 140: Prepared using General Procedure A with Variant iii) in 46% yield from Compound VI using phenyl (3-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)-5-chloro-4-methylphenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (br s, 1H), 8.77 (s, 1H), 8.30 (s, 1H), 7.69 - 7.60 (m, 2H), 7.56 (s, 2H), 7.11 (d, J = 1.9 Hz, 1H), 6.85 (br t, J = 5.9 Hz, 1H), 5.11 (dd, J = 5.0, 13.3 Hz, 1H), 4.48 - 4.36 (m, 3H), 4.35 - 4.26 (m, 1H), 4.19 (br s, 2H), 2.98 - 2.85 (m, 1H), 2.68 - 2.52 (m, 3H), 2.47 - 2.33 (m, 3H), 2.26 (s, 3H), 2.19 (br d, J = 10.6 Hz, 2H), 2.06 - 1.92 (m, 1H), 1.84 - 1.75 (m, 2H), 1.75 - 1.63 (m, 2H). MS (ESI) m/z 566.1 [M+H] ⁺

Scheme for the preparation of phenyl(3-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)-5-chloro-4-methylphenyl)carbamate.

Step 1: To a solution of 8-oxa-3-azabicyclo[3.2.1]octane (400 mg, 3.53 mmol, 1.00 equiv.) and triethylamine (0.74 mL, 5.30 mmol, 1.50 equiv.) in tetrahydrofuran (15.0 mL), 1-(bromomethyl)-3-chloro-2-methyl-5-nitrobenzene (842 mg, 3.18 mmol, 0.90 equiv.) was added. The reaction was stirred at 20°C for 6 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 5/1) to give 3-(3-chloro-2-methyl-5-nitrobenzyl)-8-oxa-3-azabicyclo[3.2.1]octane as a white solid.

Step 2: A mixture of 3-(3-chloro-2-methyl-5-nitrobenzyl)-8-oxa-3-azabicyclo[3.2.1]octane (750 mg, 2.53 mmol, 1.00 equiv.), ammonium chloride (135 mg, 2.53 mmol, 1.00 equiv.), and iron powder (706 mg, 12.6 mmol, 5.00 equiv.) in ethanol (20.0 mL) and water (10.0 mL) was stirred at 90°C for 3 hours. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 5/1) to give 3-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)-5-chloro-4-methylaniline (650 mg, 2.31 mmol, 91% yield) as a yellow solid.

Step 3: To a solution of 3-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)-5-chloro-4-methylaniline (300 mg, 1.12 mmol, 1.00 equiv.) and potassium carbonate (466 mg, 3.37 mmol, 3.00 equiv.) in acetone (3.00 mL) was added phenyl chloroformate (0.14 mL, 1.12 mmol, 1.00 equiv.) dropwise. The reaction was stirred at 15°C for 2 hours. Water (50.0 mL) was added, and the mixture was extracted with ethyl acetate (3 x 40.0 mL). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give phenyl (3-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)-5-chloro-4-methylphenyl)carbamate (400 mg, crude) as a yellow solid.

Compound 141: Prepared using General Procedure A with Variant iii) in 14% yield from Compound VI using phenyl (3-chloro-4-methyl-5-((2-methyl-1,3-dioxan-5-yl)methyl)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.73 (s, 1H), 7.66 (s, 1H), 7.60 - 7.49 (m, 3H), 7.01 (d, J = 2.0 Hz, 1H), 6.85 (br s, 1H), 5.12 (dd, J = 5.2, 13.3 Hz, 1H), 4.61 (q, J = 5.0 Hz, 1H), 4.49 - 4.27 (m, 4H), 3.86 (dd, J = 4.4, 11.6 Hz, 2H), 3.42 (t, J = 11.2 Hz, 2H), 2.99 - 2.84 (m, 1H), 2.60 (td, J = 2.0, 15.2 Hz, 1H), 2.40 (dd, J = 4.4, 13.0 Hz, 1H), 2.34 (d, J = 7.2 Hz, 2H), 2.20 (s, 3H), 2.06 - 1.95 (m, 2H), 1.16 (d, J = 5.0 Hz, 3H). MS (ESI) m/z 555.3 [M+H] ⁺

Scheme for the preparation of phenyl(3-chloro-4-methyl-5-((2-methyl-1,3-dioxan-5-yl)methyl)phenyl)carbamate.

Step 1: To a solution of 2-(3-chloro-2-methyl-5-nitrobenzyl)propane-1,3-diol (1.00 g, 3.85 mmol, 1.00 equiv.) (described in Example 132) and 1,1-dimethoxyethane (611 μL, 5.78 mmol, 1.50 equiv.) in dichloromethane (10.0 mL) was added boron trifluoride diethyl etherate (713 μL, 5.78 mmol, 1.50 equiv.). The reaction was stirred at 25°C for 1.5 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (3 x 35.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 5-(3-chloro-2-methyl-5-nitrobenzyl)-2-methyl-1,3-dioxane (1.10 g, 3.85 mmol, trans and cis, crude) as a yellow oil.

Step 2: A mixture of 5-(3-chloro-2-methyl-5-nitrobenzyl)-2-methyl-1,3-dioxane (1.10 g, 3.85 mmol, 1.00 equiv.), iron powder (1.07 g, 19.3 mmol, 5.00 equiv.), and ammonium chloride (206 mg, 3.85 mmol, 1.00 equiv.) in ethanol (10.0 mL) and water (5.00 mL) was stirred at 90°C for 10 hours. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column chromatography and lyophilized to give 3-chloro-4-methyl-5-((2-methyl-1,3-dioxan-5-yl)methyl)aniline (0.60 g, 2.35 mmol, 61% yield, trans and cis) as a gray solid.

Step 3: To a solution of 3-chloro-4-methyl-5-((2-methyl-1,3-dioxan-5-yl)methyl)aniline (0.60 g, 2.35 mmol, 1.00 equiv.) and potassium carbonate (649 mg, 4.69 mmol, 2.00 equiv.) in acetone (10.0 mL) was added phenyl chloroformate (0.35 mL, 2.82 mmol, 1.20 equiv.). The reaction was stirred at 25°C for 2 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (3 x 35.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give phenyl (3-chloro-4-methyl-5-((2-methyl-1,3-dioxan-5-yl)methyl)phenyl)carbamate (0.9 g, 2.35 mmol, trans and cis, crude) as a yellow oil, which was used directly in the next step.

Compound 142: Prepared using General Procedure A with Variant iii) in 29% yield from Compound VI using phenyl (3-chloro-5-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-4-methylphenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.24 - 10.65 (m, 1H), 8.73 (s, 1H), 7.66 (s, 1H), 7.60 - 7.53 (m, 3H), 7.01 (d, J = 2.0 Hz, 1H), 6.80 (t, J = 6.2 Hz, 1H), 5.12 (dd, J = 5.2, 13.2 Hz, 1H), 4.50 - 4.26 (m, 4H), 3.75 (dd, J = 4.2, 11.6 Hz, 2H), 3.57 (dd, J = 7.6, 11.6 Hz, 2H), 2.97 - 2.85 (m, 1H), 2.65 - 2.56 (m, 3H), 2.40 (dd, J = 4.4, 12.8 Hz, 1H), 2.22 (s, 3H), 2.06 - 1.95 (m, 1H), 1.80 (td, J = 3.8, 7.4 Hz, 1H), 1.37 (s, 3H), 1.30 (s, 3H). MS (ESI) m/z 569.2 [M+H] ⁺

Scheme for the preparation of phenyl(3-chloro-5-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-4-methylphenyl)carbamate.

Step 1: A mixture of 2-(3-chloro-2-methyl-5-nitrobenzyl)propane-1,3-diol (0.82 g, 3.16 mmol, 1.00 equiv.) (described in Example 132), 2,2-dimethoxypropane (0.43 mL, 3.47 mmol, 1.10 equiv.), and indium(III) trifluoromethanesulfonate (177 mg, 316 μmol, 0.10 equiv.) was stirred at 25°C for 0.5 h. The mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (3 x 55.0 mL). The combined organic layers were washed with brine (15.0 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 5-(3-chloro-2-methyl-5-nitrobenzyl)-2,2-dimethyl-1,3-dioxane (0.99 g, 3.16 mmol, crude) as a yellow oil. It was used directly in the next step.

Step 2: A mixture of 5-(3-chloro-2-methyl-5-nitrobenzyl)-2,2-dimethyl-1,3-dioxane (1.00 g, 3.34 mmol, 1.00 equiv.), iron powder (932 mg, 16.7 mmol, 5.00 equiv.), and ammonium chloride (178 mg, 3.34 mmol, 1.00 equiv.) in ethanol (10.0 mL) and water (5.00 mL) was stirred at 50°C for 10 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (15.0 mL) and extracted with ethyl acetate (3 x 35.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain 3-chloro-5-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-4-methylaniline (0.40 g, 1.48 mmol, 44% yield) as a yellow oil.

Step 3: To a solution of 3-chloro-5-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-4-methylaniline (0.40 g, 1.48 mmol, 1.00 equiv.) and potassium carbonate (410 mg, 2.97 mmol, 2.00 equiv.) in acetone (5.00 mL) was added phenyl chloroformate (0.22 mL, 1.78 mmol, 1.20 equiv.). The reaction was stirred at 25°C for 2 hours. The mixture was diluted with water (15.0 mL) and extracted with ethyl acetate (3 x 35.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give phenyl (3-chloro-5-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-4-methylphenyl)carbamate (0.55 g, 1.48 mmol, crude) as a yellow oil, which was used directly in the next step.

Compound 143: Prepared using General Procedure A with Variant iii) in 44% yield from Compound VI using phenyl (3-chloro-4-methyl-5-(trifluoromethoxy)phenyl)carbamate.

¹ H NMR (400MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 9.10 (s, 1H), 7.67 (s, 1H), 7.58 - 7.55 (m, 3H), 7.54 (d, J = 1.2 Hz, 1H), 7.00 (t, J = 6.0 Hz, 1H), 5.12 (dd, J = 5.2, 13.6 Hz, 1H), 4.47 - 4.39 (m, 3H), 4.34 - 4.28 (m, 1H), 2.96 - 2.87 (m, 1H), 2.64 - 2.57 (m, 1H), 2.47 - 2.36 (m, 1H), 2.20 (s, 3H), 2.00 (dtd, J = 2.0, 5.2, 12.4 Hz, 1H). MS (ESI) m/z 525.0 [M+H] ⁺

Scheme for the preparation of phenyl(3-chloro-4-methyl-5-(trifluoromethoxy)phenyl)carbamate.

Step 1: To a solution of 3-chloro-5-(trifluoromethoxy)aniline (1.60 g, 7.56 mmol, 1.00 equiv.) in dimethylformamide (20.0 mL) was added N-bromosuccinimide (1.35 g, 7.56 mmol, 1.00 equiv.). The reaction was stirred at 25°C for 12 hours. The mixture was poured into water (120 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (3 x 60.0 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-bromo-3-chloro-5-(trifluoromethoxy)aniline (2.10 g, 7.23 mmol, 96% yield) as a yellow oil.

Step 2: To a mixture of 4-bromo-3-chloro-5-(trifluoromethoxy)aniline (1.00 g, 3.44 mmol, 1.00 equiv.), methylboronic acid (824 mg, 13.8 mmol, 4.00 equiv.), and cesium carbonate (3.37 g, 10.3 mmol, 3.00 equiv.) in dioxane (10.0 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (252 mg, 344 μmol, 0.100 equiv.) under nitrogen. The reaction was stirred at 100°C for 3 hours. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1 to 2/1) to obtain 3-chloro-4-methyl-5-(trifluoromethoxy)aniline (700 mg, 3.10 mmol, 90% yield) as a brown oil.

Step 3: To a solution of 3-chloro-4-methyl-5-(trifluoromethoxy)aniline (600 mg, 2.66 mmol, 1.00 equiv.) and pyridine (0.64 mL, 7.98 mmol, 3.00 equiv.) in acetonitrile (10.0 mL), phenyl chloroformate (0.50 mL, 3.99 mmol, 1.50 equiv.) was added. The reaction was stirred at 20°C for 3 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 40/1) to give phenyl (3-chloro-4-methyl-5-(trifluoromethoxy)phenyl)carbamate (800 mg, 2.31 mmol, 87% yield) as a white solid.

Compound 144: Prepared using General Procedure A with Variant iii) in 59% yield from Compound VI using phenyl(4-methyl-3-(trifluoromethoxy)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.88 (s, 1H), 7.69 - 7.63 (m, 2H), 7.60 - 7.53 (m, 2H), 7.25 - 7.20 (m, 1H), 7.20 - 7.14 (m, 1H), 6.83 (t, J = 6.0 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.46 - 4.28 (m, 4H), 2.97 - 2.86 (m, 1H), 2.63 - 2.57 (m, 1H), 2.40 (dq, J = 4.5, 13.2 Hz, 1H), 2.18 (s, 3H), 2.00 (dtd, J = 2.1, 5.2, 12.6 Hz, 1H). MS (ESI) m/z 491.2 [M+H] ⁺

Scheme for the preparation of phenyl(4-methyl-3-(trifluoromethoxy)phenyl)carbamate.

Step 1: To a solution of 2-methyl-5-nitrophenol (2.00 g, 13.1 mmol, 1.00 equivalents), silver trifluoromethanesulfonate (16.8 g, 65.3 mmol, 5.00 equivalents), 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (9.25 g, 26.1 mmol, 2.00 equivalents), N-fluorobenzenesulfonimide (8.24 g, 26.1 mmol, 2.00 equivalents), and cesium fluoride (11.9 g, 78.4 mmol, 6.00 equivalents) in toluene (100 mL) was added trimethyl(trifluoromethyl)silane (9.29 g, 65.3 mmol, 5.00 equivalents) and 2-fluoropyridine (5.61 mL, 65.3 mmol, 5.00 equivalents) under a nitrogen atmosphere. The reaction mixture was stirred under nitrogen at 20°C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was diluted with water (100 mL) and extracted with petroleum ether/ethyl acetate (10/1, 100 mL). The organic layer was washed with water (20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 20/1) to give 1-methyl-4-nitro-2-(trifluoromethoxy)benzene (1.60 g, crude) as a yellow oil.

Step 2: To a solution of 1-methyl-4-nitro-2-(trifluoromethoxy)benzene (1.60 g, 7.24 mmol, 1.00 equiv.) in methanol (20.0 mL) and water (20.0 mL), iron powder (2.83 g, 50.7 mmol, 7.00 equiv.) and ammonium chloride (2.71 g, 50.7 mmol, 7.00 equiv.) were added. The reaction was stirred at 80°C for 2 hours. The mixture was concentrated under reduced pressure to give a residue. Ethyl acetate (50.0 mL) was added to the residue, and the mixture was washed with water (20.0 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 5/1) to obtain 4-methyl-3-(trifluoromethoxy)aniline (460 mg, 2.41 mmol, 33% yield) as a yellow oil.

Step 3: To a mixture of 4-methyl-3-(trifluoromethoxy)aniline (200 mg, 1.05 mmol, 1.00 equiv.) and potassium carbonate (174 mg, 1.26 mmol, 1.20 equiv.) in acetone (4.00 mL), phenyl chloroformate (180 mg, 1.15 mmol, 1.10 equiv.) was added. The reaction was stirred at 20°C for 1 hour. The mixture was diluted with water (3.00 mL), extracted with ethyl acetate (5.00 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give phenyl(4-methyl-3-(trifluoromethoxy)phenyl)carbamate (300 mg, 964 μmol, 92% yield) as a clear oil.

Compound 145: Prepared using General Procedure A with Variant iii) and phenyl (3-chloro-4-methyl-5-((2-methyl-1,3-dioxan-5-yl)methyl)phenyl)carbamate in 2% yield from Compound VI.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (br s, 1H), 8.86 (s, 1H), 8.44 (s, 1H), 7.69 - 7.59 (m, 2H), 7.56 (d, J = 0.8 Hz, 2H), 6.98 (d, J = 2.0 Hz, 1H), 6.85 (t, J = 6.0 Hz, 1H), 5.12 (dd, J = 5.2, 13.4 Hz, 1H), 4.69 (q, J = 5.0 Hz, 1H), 4.50 - 4.26 (m, 4H), 3.87 - 3.77 (m, 2H), 3.70 (d, J = 11.0 Hz, 2H), 2.99 - 2.82 (m, 3H), 2.66 - 2.56 (m, 1H), 2.46 - 2.32 (m, 1H), 2.23 (s, 3H), 2.06 - 1.96 (m, 1H), 1.54 (br t, J = 7.2 Hz, 1H), 1.22 (d, J = 5.0 Hz, 3H). MS (ESI) m/z 555.1 [M+H] ⁺

Compound 146: Prepared using General Procedure A with Variant iii) in 74% yield from Compound VI using phenyl(3-methylisothiazol-5-yl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 10.38 (s, 1H), 7.65 (s, 1H), 7.59 - 7.53 (m, 2H), 7.30 (br t, J = 5.7 Hz, 1H), 6.51 (s, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.47 - 4.43 (m, 1H), 4.41 (s, 2H), 4.34 - 4.27 (m, 1H), 2.97 - 2.84 (m, 1H), 2.59 (br d, J = 16.8 Hz, 1H), 2.46 - 2.34 (m, 1H), 2.24 (s, 3H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 414.1 [M+H] ⁺

Scheme for the preparation of phenyl(3-methylisothiazol-5-yl)carbamate.

Step 1: To a solution of 3-methylisothiazol-5-amine hydrochloride (0.260 g, 1.73 mmol, 1.30 equivalents, hydrochloride salt) in pyridine (2.00 mL) was added phenyl chloroformate (166 μL, 1.33 mmol, 1.00 equivalents). The reaction was stirred at 0°C for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was washed with water to give phenyl (3-methylisothiazol-5-yl)carbamate (250 mg, 1.07 mmol, 80% yield) as a yellow solid.

Compound 147: Prepared using General Procedure A with Variant iii) in 60% yield from Compound VI using phenyl(5-methylthiazol-2-yl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.00 (s, 1H), 10.38 (br s, 1H), 7.64 (s, 1H), 7.59 - 7.52 (m, 2H), 7.11 (br s, 1H), 6.96 (d, J = 1.2 Hz, 1H), 5.12 (dd, J = 5.1, 13.4 Hz, 1H), 4.48 - 4.24 (m, 4H), 2.97 - 2.84 (m, 1H), 2.69 - 2.55 (m, 1H), 2.45 - 2.31 (m, 1H), 2.27 (d, J = 1.1 Hz, 3H), 2.05 - 1.94 (m, 1H). MS (ESI) m/z 414.1 [M+H] ⁺

Scheme for the preparation of phenyl(5-methylthiazol-2-yl)carbamate.

Step 1: To a mixture of 5-methylthiazol-2-amine (500 mg, 4.38 mmol, 1.00 equiv.) and pyridine (1.06 mL, 13.1 mmol, 3.00 equiv.) in dichloromethane (5.00 mL), phenyl chloroformate (575 μL, 4.60 mmol, 1.05 equiv.) was added dropwise over 20 minutes at 0°C under nitrogen. The reaction was stirred at 0°C for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford phenyl (5-methylthiazol-2-yl)carbamate (300 mg, 1.28 mmol, 29% yield) as a white solid.

Compound 148: Prepared using General Procedure A with Variant iii) in 52% yield from Compound VI using phenyl(5-ethylthiazol-2-yl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1 H), 10.39 (br s, 1 H), 7.65 (s, 1 H), 7.56 (s, 2 H), 7.13 (br s, 1 H), 6.99 (s, 1 H), 5.11 (dd, J = 13, 5.2 Hz, 1 H), 4.48 - 4.43 (m, 1 H), 4.42 (d, J = 5.8 Hz, 2 H), 4.34 - 4.27 (m, 1 H), 2.98 - 2.84 (m, 1 H), 2.67 (q, J = 7.4 Hz, 2 H), 2.59 (br d, J = 18 Hz, 1 H), 2.40 (br d, J = 13 Hz, 1 H), 2.05 - 1.96 (m, 1 H), 1.18 (t, J = 7.6 Hz, 3 H). MS (ESI) m/z 428.2 [M+H] ⁺

Scheme for the preparation of phenyl(5-ethylthiazol-2-yl)carbamate.

Step 1: To a solution of 5-ethylthiazol-2-amine (200 mg, 1.56 mmol, 1.00 equiv.) and pyridine (5.00 mL) in dichloromethane (10.0 mL) under nitrogen at 0°C, phenyl chloroformate (235 μL, 1.87 mmol, 1.20 equiv.) was added. The reaction was stirred at 25°C for 12 hours. The mixture was extracted with ethyl acetate (3 x 10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give phenyl(5-ethylthiazol-2-yl)carbamate (309 mg, 1.24 mmol, 80% yield) as a white solid.

Compound 149: Prepared using General Procedure A with Variant iii) in 50% yield from Compound VI using phenyl (3-(trifluoromethyl)isothiazol-5-yl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.88 - 10.60 (m, 2H), 7.69 (s, 1H), 7.63 - 7.47 (m, 3H), 7.06 (s, 1H), 5.08 (dd, J = 5.2, 13.1 Hz, 1H), 4.55 - 4.27 (m, 4H), 2.99 - 2.80 (m, 1H), 2.70 - 2.58 (m, 1H), 2.44 - 2.33 (m, 1H), 2.12 - 1.92 (m, 1H). MS (ESI) m/z 468.0 [M+H] ⁺

Scheme for the preparation of phenyl(3-(trifluoromethyl)isothiazol-5-yl)carbamate.

Step 1: To a solution of potassium tert-butoxide (1 M, 84.3 mL, 1.60 equiv.) at 0°C was added dropwise a solution of ethyl 2,2,2-trifluoroacetate (7.27 mL, 52.7 mmol, 1.00 equiv.) in acetonitrile (3.19 mL, 60.6 mmol, 1.15 equiv.) at 0°C. The reaction was stirred at 20°C for 24 hours. The reaction was quenched with hydrochloric acid (50.0 mL, 1 M) and extracted with ethyl acetate (3 x 50.0 mL). The combined organic phase was washed with brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 4,4,4-trifluoro-3-oxobutanenitrile (10.0 g, crude) as a yellow oil, which was used directly in the next step.

Step 2: In a Dean-Stark apparatus, a mixture of 4,4,4-trifluoro-3-oxobutanenitrile (6.00 g, 43.8 mmol, 1.00 equiv.), ammonium formate (8.28 g, 131 mmol, 3.00 equiv.), and acetic acid (0.25 mL, 4.38 mmol, 0.100 equiv.) in toluene (10.0 mL) was heated to reflux for 18 hours. The mixture was concentrated under reduced pressure to give (Z)-3-amino-4,4,4-trifluorobut-2-enenitrile (6.00 g, crude) as a yellow oil, which was used directly in the next step.

Step 3: To a solution of (Z)-3-amino-4,4,4-trifluorobut-2-enenitrile (6.00 g, 44.1 mmol, 1.00 equiv.) in dimethylformamide (30.0 mL), magnesium chloride (1.81 mL, 44.1 mmol, 1.00 equiv.) and sodium hydrosulfide (4.94 g, 88.2 mmol, 2.00 equiv.) were added in small portions. The reaction was stirred at 25°C for 18 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (5 x 20.0 mL). The combined organic phase was washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford (Z)-3-amino-4,4,4-trifluorobut-2-enethioamide (3.00 g, crude) as a black oil, which was used directly in the next step.

Step 4: To an ice-cooled mixture of (Z)-3-amino-4,4,4-trifluorobut-2-enethioamide (1.50 g, 8.82 mmol, 1.00 equiv.) in pyridine (10.0 mL) at 0°C was added 30% pure hydrogen peroxide (1.69 mL, 17.6 mmol, 2.00 equiv.). The mixture was stirred at 25°C for 2 hours. The mixture was dried under nitrogen to give a residue. The residue was diluted with aqueous sodium sulfite (20.0 mL) and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layers were washed with saturated aqueous citric acid (2 x 20.0 mL) and brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1 to 1/1) to obtain 3-(trifluoromethyl)isothiazol-5-amine (150 mg, 892 μmol, 10% yield) as a yellow oil.

Step 5: To a solution of 3-(trifluoromethyl)isothiazol-5-amine (250 mg, 1.49 mmol, 1.00 equiv.) in pyridine (2.00 mL) was added dropwise phenyl chloroformate (0.28 mL, 2.23 mmol, 1.50 equiv.) at 0°C. The reaction was stirred at 25°C for 4 hours. The mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (2 x 10.0 mL). The combined organic phase was washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 30/1 to 10/1) to give phenyl (3-(trifluoromethyl)isothiazol-5-yl)carbamate (400 mg, 1.39 mmol, 93% yield) as a white solid.

Compound 150: Prepared using General Procedure A with Variant iii) in 54% yield from Compound VI using phenyl(4,5-dimethylthiazol-2-yl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.00 (s, 1H), 10.29 (br s, 1H), 7.64 (s, 1H), 7.60 - 7.52 (m, 2H), 7.13 (br s, 1H), 5.12 (dd, J = 5.0, 13.2 Hz, 1H), 4.48 - 4.43 (m, 1H), 4.41 (s, 2H), 4.35 - 4.26 (m, 1H), 2.98 - 2.85 (m, 1H), 2.59 (br d, J = 17.3 Hz, 1H), 2.43 - 2.35 (m, 1H), 2.17 (s, 3H), 2.08 (s, 3H), 2.04 - 1.94 (m, 1H). MS (ESI) m/z 428.1 [M+H] ⁺

Scheme for the preparation of phenyl(4,5-dimethylthiazol-2-yl)carbamate.

Step 1: To a solution of 4,5-dimethylthiazol-2-amine (0.200 g, 1.56 mmol, 1.00 equiv.) and pyridine (0.38 mL, 4.68 mmol, 3.00 equiv.) in dichloromethane (2.00 mL) at 0°C, phenyl chloroformate (0.20 mL, 1.64 mmol, 1.05 equiv.) was added dropwise. The reaction was stirred at 0°C for 2 hours. Additional phenyl chloroformate (49.0 μL, 390 μmol, 0.25 equiv.) was added, and the reaction was stirred at 0°C for 1 hour. Water (2.00 mL) was added slowly over 30 minutes, and the mixture was diluted with dichloromethane (10 mL). The organic layer was washed with saturated aqueous sodium carbonate (3.00 mL) and brine (2.00 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was triturated with ethyl acetate/petroleum ether (1:5) at 25°C for 30 minutes to give phenyl(4,5-dimethylthiazol-2-yl)carbamate (80.0 mg, 322 μmol, 21% yield) as a white solid.

Compound 151: Prepared using General Procedure A with Variant iii) in 60% yield from Compound VI using phenyl (4-methyl-3-(morpholinomethyl)-5-(trifluoromethoxy)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 8.91 (s, 1H), 8.16 (s, 1H), 7.70 - 7.64 (m, 1H), 7.64 - 7.60 (m, 1H), 7.60 - 7.52 (m, 2H), 7.17 (d, J = 2.2 Hz, 1H), 6.79 (t, J = 6.0 Hz, 1H), 5.11 (dd, J = 5.0, 13.3 Hz, 1H), 4.49 - 4.25 (m, 4H), 3.56 (br t, J = 4.3 Hz, 4H), 3.40 (s, 2H), 2.96 - 2.85 (m, 1H), 2.63 - 2.56 (m, 1H), 2.46 - 2.33 (m, 5H), 2.16 (s, 3H), 2.03 - 1.96 (m, 1H). MS (ESI) m/z 590.3 [M+H] ⁺

Scheme for the preparation of phenyl(4-methyl-3-(morpholinomethyl)-5-(trifluoromethoxy)phenyl)carbamate.

Step 1: To a solution of 2-methyl-5-nitrobenzoic acid (10.0 g, 55.2 mmol, 1.00 equiv.) in sulfuric acid (20.0 mL) was added N-iodosuccinimide (14.9 g, 66.3 mmol, 1.20 equiv.). The reaction was stirred at 60°C for 2 hours. The mixture was diluted with ice water (200 mL) and filtered. The filter cake was washed with water (100 mL) and dried under vacuum to give 3-iodo-2-methyl-5-nitrobenzoic acid (16.0 g, 52.1 mmol, 94% yield) as a white solid.

Step 2: To a solution of 3-iodo-2-methyl-5-nitrobenzoic acid (5.00 g, 16.3 mmol, 1.00 equiv.), copper iodide (310 mg, 1.63 mmol, 0.10 equiv.), and quinolin-8-ol (563 μL, 3.26 mmol, 0.20 equiv.) in water (3.00 mL) and dimethyl sulfoxide (3.00 mL), a solution of potassium hydroxide (3.65 g, 65.1 mmol, 4.00 equiv.) was added. The reaction was stirred at 100°C for 12 hours. The mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (2 x 50.0 mL). The combined organic layers were washed with water (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-hydroxy-2-methyl-5-nitro-benzoic acid (3.20 g, crude) as a brown solid, which was used directly in the next step.

Step 3: To a solution of 3-hydroxy-2-methyl-5-nitrobenzoic acid (3.20 g, 16.2 mmol, 1.00 equivalents) and morpholine (1.71 mL, 19.5 mmol, 1.20 equivalents) in dichloromethane (100 mL) was added triethylamine (2.26 mL, 16.2 mmol, 1.00 equivalents) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (7.41 g, 19.5 mmol, 1.20 equivalents) at 20°C. The reaction was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1 to 0/1) to give (3-hydroxy-2-methyl-5-nitrophenyl)-morpholino-methanone (1.40 g, crude) as a yellow solid.

Step 4: (3-hydroxy-2-methyl-5-nitrophenyl)-morpholino-methanone (1.30 g, 4.88 mmol, 1.00 equivalents), silver trifluoromethanesulfonate (6.27 g, 24.4 mmol, 5.00 equivalents), 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (3.46 g, 9.77 mmol, 2.00 equivalents) To a solution of N-fluorobenzenesulfonimide (3.08 g, 9.77 mmol, 2.00 equiv.) and cesium fluoride (4.45 g, 29.3 mmol, 1.08 mL, 6.00 equiv.) in toluene (130 mL) under nitrogen was added trimethyl(trifluoromethyl)silane (3.47 g, 24.4 mmol, 5.00 equiv.) and 2-fluoropyridine (2.10 mL, 24.4 mmol, 5.00 equiv.). The reaction was stirred under nitrogen at 20°C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 2/1) to obtain (2-methyl-5-nitro-3-(trifluoromethoxy)phenyl)(morpholino)methanone (1.00 g, crude) as a yellow solid.

Step 5: To a solution of (2-methyl-5-nitro-3-(trifluoromethoxy)phenyl)-morpholino-methanone (900 mg, 2.69 mmol, 1.00 equiv.) in tetrahydrofuran (15.0 mL) was added borane dimethyl sulfide complex (10.0 M, 539 μL, 2.00 equiv.) at 0°C. The reaction was stirred at 60°C for 30 minutes. The mixture was quenched with methanol (2.00 mL) and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column chromatography to give 4-(2-methyl-5-nitro-3-(trifluoromethoxy)benzyl)morpholine (410 mg, 1.28 mmol, 48% yield) as a yellow oil.

Step 6: To a solution of 4-(2-methyl-5-nitro-3-(trifluoromethoxy)benzyl)morpholine (400 mg, 1.25 mmol, 1.00 equiv.) in methanol (5.00 mL) and water (5.00 mL), iron powder (488 mg, 8.74 mmol, 7.00 equiv.) and ammonium chloride (468 mg, 8.74 mmol, 7.00 equiv.) were added. The reaction was stirred at 80°C for 2 hours. The mixture was diluted with saturated sodium carbonate (1.00 mL) and extracted with ethyl acetate (2 x 10.0 mL). The combined organic layers were washed with water (5.00 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1 to 1/1) to obtain 4-methyl-3-(morpholinomethyl)-5-(trifluoromethoxy)aniline (270 mg, 930 μmol, 74% yield) as a yellow oil.

Step 7: To a solution of 4-methyl-3-(morpholinomethyl)-5-(trifluoromethoxy)aniline (100 mg, 344 μmol, 1.00 equiv.) and potassium carbonate (57.1 mg, 413 μmol, 1.20 equiv.) in acetone (1.00 mL) was added phenyl chloroformate (47 μL, 379 μL, 1.10 equiv.) at 25°C. The reaction was stirred at 25°C for 1 hour. The mixture was diluted with water (6.00 mL) and extracted with ethyl acetate (10.0 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give phenyl (4-methyl-3-(morpholinomethyl)-5-(trifluoromethoxy)phenyl)carbamate (141 mg, crude) as a clear oil, which was used directly in the next step.

Compound 152: Prepared using General Procedure A with Variant iii) in 78% yield from Compound VI using phenyl 3-chloro-4-methylbenzylcarbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (br s, 1H), 8.49 (s, 1H), 7.63 (s, 1H), 7.56 - 7.48 (m, 2H), 7.29 - 7.23 (m, 2H), 7.13 - 7.08 (m, 1H), 6.68 - 6.53 (m, 2H), 5.15 - 5.07 (m, 1H), 4.46 - 4.38 (m, 1H), 4.35 - 4.26 (m, 3H), 4.19 (d, J = 6.0 Hz, 2H), 2.98 - 2.84 (m, 1H), 2.63 - 2.58 (m, 1H), 2.43 - 2.31 (m, 1H), 2.28 (s, 3H), 2.05 - 1.93 (m, 1H). MS (ESI) m/z 455.2 [M+H] ⁺

Scheme for the preparation of phenyl 3-chloro-4-methylbenzylcarbamate.

Step 1: To a solution of (3-chloro-4-methyl-phenyl)methanamine (500 mg, 3.21 mmol, 1.00 equiv.) and pyridine (0.78 mL, 9.64 mmol, 3.00 equiv.) in acetonitrile (5.00 mL) was added phenyl chloroformate (0.60 mL, 4.82 mmol, 1.50 equiv.). The reaction was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with ethyl acetate (30.0 mL) and water (50.0 mL). The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (3 x 30.0 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain phenyl 3-chloro-4-methylbenzylcarbamate (632 mg, 2.29 mmol, 71% yield) as a white solid.

Compound 153: Prepared using General Procedure A with Variant iii) in 19% yield from Compound VI using phenylbenzo[d][1,3]dioxol-5-ylcarbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (s, 1H), 8.49 (s, 1H), 7.65 (s, 1H), 7.55 (d, J = 1.0 Hz, 2H), 7.17 (d, J = 2.0 Hz, 1H), 6.80 - 6.74 (m, 1H), 6.72 - 6.68 (m, 1H), 6.65 (t, J = 6.0 Hz, 1H), 5.93 (s, 2H), 5.14 - 5.08 (m, 1H), 4.47 - 4.27 (m, 4H), 2.97 - 2.84 (m, 1H), 2.64 - 2.56 (m, 1H), 2.43 - 2.31 (m, 1H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 437.3 [M+H] ⁺

Scheme for the preparation of phenylbenzo[d][1,3]dioxol-5-ylcarbamates.

Step 1: To a solution of benzo[d][1,3]dioxol-5-amine (1.00 g, 7.29 mmol, 1.00 equiv.) and pyridine (1.77 mL, 21.9 mmol, 3.00 equiv.) in acetonitrile (10 mL) was added phenyl chloroformate (1.37 mL, 11.0 mmol, 1.50 equiv.). The reaction was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with ethyl acetate (30 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to give phenyl benzo[d][1,3]dioxol-5-ylcarbamate (1.80 g, crude) as a pale yellow solid.

Compound 154: Prepared using General Procedure A with Variant iii) in 21% yield from Compound VI using phenyl (3-(1,4-diazabicyclo[3.2.1]octan-4-ylmethyl)-5-chloro-4-methylphenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (br s, 1H), 8.95 (s, 1H), 8.28 (s, 1H), 7.66 (s, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.56 (d, J = 0.7 Hz, 2H), 7.15 (s, 1H), 7.08 - 6.96 (m, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.47 - 4.27 (m, 4H), 3.40 - 3.35 (m, 1H), 3.30 - 3.27 (m, 1H), 3.18 - 3.14 (m, 1H), 2.96 - 2.81 (m, 5H), 2.67 - 2.53 (m, 4H), 2.46 - 2.35 (m, 2H), 2.26 (s, 3H), 2.11 - 1.95 (m, 2H), 1.60 - 1.46 (m, 1H). MS (ESI) m/z 565.3 [M+H] ⁺

Scheme for the preparation of phenyl(3-(1,4-diazabicyclo[3.2.1]octan-4-ylmethyl)-5-chloro-4-methylphenyl)carbamate.

Step 1: To a solution of 2-methyl-5-nitrobenzoic acid (5.00 g, 27.6 mmol, 1.00 equiv.) in sulfuric acid (10.0 mL) at 80°C, 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (6.53 g, 33.1 mmol, 1.20 equiv.) was added dropwise. The reaction was stirred at 80°C for 12 hours. The mixture was poured into ice water (100 mL) and filtered. The filter cake was dissolved in ethyl acetate (200 mL), and the organic layer was washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-chloro-2-methyl-5-nitrobenzoic acid (5.00 g, 23.2 mmol, 84% yield) as a white solid.

Step 2: To a solution of 3-chloro-2-methyl-5-nitrobenzoic acid (388 mg, 1.80 mmol, 1.00 equiv.) and 1,4-diazabicyclo[3.2.1]octane dihydrochloride (300 mg, 1.62 mmol, 0.90 equiv., dihydrochloride salt) in dichloromethane (5.00 mL) was added triethylamine (0.75 mL, 5.40 mmol, 3.00 equiv.) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (822 mg, 2.16 mmol, 1.20 equiv.) at 20°C. The reaction was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure to provide a residue. The residue was diluted with water (20.0 mL) and saturated aqueous sodium carbonate (3.00 mL) and then extracted with ethyl acetate (50.0 mL). The organic layer was washed with water (10.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (3-chloro-2-methyl-5-nitro-phenyl)-(1,4-diazabicyclo[3.2.1]octan-4-yl)methanone (600 mg, crude) as a yellow solid, which was used directly in the next step.

Step 3: To a solution of (3-chloro-2-methyl-5-nitro-phenyl)-(1,4-diazabicyclo[3.2.1]octan-4-yl)methanone (700 mg, 2.26 mmol, 1.00 equiv.) in tetrahydrofuran (20.0 mL) was added borane dimethyl sulfide complex (10.0 M, 0.45 mL, 2.00 equiv.) at 0°C. The reaction was stirred at 60°C for 30 minutes. The mixture was quenched with methanol (0.500 mL) and concentrated under reduced pressure to give a residue. The residue was diluted with water (10.0 mL) and saturated aqueous sodium carbonate (10.0 mL) and then extracted with ethyl acetate (30.0 mL). The organic layer was washed with water (10.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 2/1) to obtain 4-(3-chloro-2-methyl-5-nitrobenzyl)-1,4-diazabicyclo[3.2.1]octane (150 mg, 507 μmol, 22% yield) as a white solid.

Step 4: To a solution of 4-(3-chloro-2-methyl-5-nitrobenzyl)-1,4-diazabicyclo[3.2.1]octane (150 mg, 507 μmol, 1.00 equiv.) in methanol (1.50 mL) and water (1.50 mL), iron powder (198 mg, 3.55 mmol, 7.00 equiv.) and ammonium chloride (190 mg, 3.55 mmol, 7.00 equiv.) were added. The reaction was stirred at 80°C for 2 hours. The mixture was diluted with saturated aqueous sodium carbonate (1.00 mL) and extracted with ethyl acetate (2 x 10.0 mL). The organic layer was washed with water (5.00 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3-(1,4-diazabicyclo[3.2.1]octan-4-ylmethyl)-5-chloro-4-methylaniline (120 mg, crude) as a yellow oil, which was used directly in the next step.

Step 5: To a solution of 3-(1,4-diazabicyclo[3.2.1]octan-4-ylmethyl)-5-chloro-4-methylaniline (100 mg, 376 μmol, 1.00 equiv.) and potassium carbonate (62.4 mg, 452 μmol, 1.20 equiv.) in acetone (2.00 mL) was added phenyl chloroformate (51.8 μL, 414 μmol, 1.10 equiv.) at 25°C. The reaction was stirred at 25°C for 1 hour. The mixture was diluted with water (3.00 mL) and extracted with ethyl acetate (5.00 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give phenyl (3-(1,4-diazabicyclo[3.2.1]octan-4-ylmethyl)-5-chloro-4-methylphenyl)carbamate (145 mg, crude) as a clear oil, which was used directly in the next step.

Compound 155: Prepared using General Procedure A with Variant iii) in 11% yield from Compound VI using phenyl (3-chloro-4-methyl-5-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (br s, 1H), 9.02 (s, 1H), 8.31 (s, 1H), 7.71 - 7.50 (m, 4H), 7.19 (d, J = 2.0 Hz, 1H), 7.06 (br s, 1H), 5.12 (dd, J = 5.2, 13.2 Hz, 1H), 4.52 - 4.25 (m, 4H), 3.12 - 2.85 (m, 4H), 2.63 - 2.57 (m, 1H), 2.40 (br dd, J = 4.2, 13.2 Hz, 1H), 2.31 (s, 3H), 2.26 (s, 3H), 2.19 (d, J = 8.6 Hz, 1H), 2.06 - 1.94 (m, 1H), 1.63 (td, J = 3.6, 7.6 Hz, 1H), 1.32 - 1.13 (m, 1H), 0.59 (dd, J = 3.6, 8.0 Hz, 1H). MS (ESI) m/z 536.3 [M+H] ⁺

Scheme for the preparation of phenyl(3-chloro-4-methyl-5-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)carbamate.

Step 1: A solution of 1-(bromomethyl)-3-chloro-2-methyl-5-nitrobenzene (25.0 g, 94.5 mmol, 1.00 equiv.) and sodium cyanide (6.02 g, 123 mmol, 1.30 equiv.) in acetonitrile (270 mL) and water (36.0 mL) was stirred under nitrogen at 80°C for 10 hours. The reaction was quenched by adding saturated aqueous sodium carbonate (60.0 mL), and the mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 0/1 to 1/4) to give 2-(3-chloro-2-methyl-5-nitrophenyl)acetonitrile (17.9 g, 85.0 mmol, 90% yield) as a white solid.

Step 2: A mixture of 2-(3-chloro-2-methyl-5-nitrophenyl)acetonitrile (17.9 g, 85.0 mmol, 1.00 equiv.), iron powder (23.7 g, 425 mmol, 5.00 equiv.), and ammonium chloride (4.55 g, 85.0 mmol, 1.00 equiv.) in ethanol (160 mL) and water (80.0 mL) was stirred at 60°C for 10 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (80.0 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (3 x 50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain 2-(5-amino-3-chloro-2-methylphenyl)acetonitrile (14.7 g, 81.4 mmol, 96% yield) as a yellow oil.

Step 3: A mixture of 2-(5-amino-3-chloro-2-methylphenyl)acetonitrile (14.7 g, 81.4 mmol, 1.00 equiv.), hexane-2,5-dione (9.29 g, 81.4 mmol, 9.55 mL, 1.00 equiv.), and p-toluenesulfonic acid monohydrate (0.16 g, 841 μmol, 0.002 equiv.) in toluene (150 mL) was stirred at 110°C for 10 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give 2-(3-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)acetonitrile (15.0 g, 58.0 mmol, 71% yield) as a yellow solid.

Step 4: To a solution of sodium hexamethyldisilazane (1.00 M, 34.8 mL, 1.80 equiv.) in tetrahydrofuran (50.0 mL) was added 2-(3-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)acetonitrile (5.00 g, 19.3 mmol, 1.00 equiv.) at -10°C. After 12 minutes, 2-(chloromethyl)oxirane (2.23 g, 24.2 mmol, 1.89 mL, 1.25 equiv.) was added, and the reaction was stirred at 25°C for 12 hours. The reaction was quenched with water (20.0 mL), and the mixture was extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain 1-(3-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-2-(hydroxymethyl)cyclopropanecarbonitrile (3.00 g, 9.53 mmol, 49% yield) as a yellow solid.

Step 5: To a solution of 1-(3-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-2-(hydroxymethyl)cyclopropanecarbonitrile (3.50 g, 11.1 mmol, 1.00 equiv.) in tetrahydrofuran (40.0 mL) was added borane dimethyl sulfide complex (10.0 M, 3.34 mL, 3.00 equiv.) at 0°C. The reaction was stirred at 50°C for 0.5 hours. The reaction was quenched by adding methanol (35.0 mL) and concentrated under reduced pressure to give (2-(aminomethyl)-2-(3-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)cyclopropyl)methanol (3.50 g, 11.1 mmol, crude) as a yellow solid, which was used directly in the next step.

Step 6: To a solution of (2-(aminomethyl)-2-(3-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)cyclopropyl)methanol (3.50 g, 11.0 mmol, 1.00 equivalents) and triphenylphosphine (3.46 g, 13.2 mmol, 1.20 equivalents) in tetrahydrofuran (35.0 mL) was added diisopropyl azodicarboxylate (2.56 mL, 13.2 mmol, 1.20 equivalents) at 0°C. The reaction was stirred at 25°C for 10 hours. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified twice by reverse-phase column chromatography and lyophilized to give 1-(3-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-3-azabicyclo[3.1.0]hexane (0.20 g, 565 μmol, 5.15% yield) as a yellow oil.

Step 7: To a solution of 1-(3-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-3-azabicyclo[3.1.0]hexane (0.20 g, 577 μmol, 1.00 equiv.), sodium cyanoborohydride (109 mg, 1.73 mmol, 3.00 equiv.), and formaldehyde (37% purity) (1.67 mL, 22.4 mmol, 38.8 equiv.) in methanol (5.00 mL) was added acetic acid (33.0 μL, 577 μmol, 1.00 equiv.). The reaction was stirred at 25°C for 2 hours. The mixture was diluted with water (10.0 mL) and extracted with dichloromethane (3 x 30.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1-(3-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-3-methyl-3-azabicyclo[3.1.0]hexane (0.10 g, 577 μmol, crude) as a yellow oil, which was used directly in the next step.

Step 8: A solution of 1-(3-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-3-methyl-3-azabicyclo[3.1.0]hexane (0.10 g, 318 μmol, 1.00 equivalents) and hydroxylamine hydrochloride (221 mg, 3.18 mmol, 10.0 equivalents) in ethanol (1.00 mL) and water (0.50 mL) was stirred at 100°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column chromatography and lyophilized to give 3-chloro-4-methyl-5-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)aniline (50.0 mg, 211 μmol, 67% yield) as a yellow oil.

Step 9: To a solution of 3-chloro-4-methyl-5-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)aniline (50.0 mg, 211 μmol, 1.00 equiv.) and potassium carbonate (58.4 mg, 422 μmol, 2.00 equiv.) in acetone (1.00 mL) was added phenyl chloroformate (31.7 μL, 253 μmol, 1.20 equiv.). The reaction was stirred at 25°C for 10 hours. The mixture was diluted with water (8.00 mL) and extracted with ethyl acetate (3 x 30.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give phenyl (3-chloro-4-methyl-5-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)carbamate (0.80 g, 253 μmol, crude) as a yellow oil, which was used directly in the next step.

Compound 156: Scheme for the preparation of compound 156.

Step 1: To a solution of (3-chloro-2-methyl-5-nitrophenyl)methanol (1.00 g, 4.96 mmol, 1.00 equivalents) and imidazole (675 mg, 9.92 mmol, 2.00 equivalents) in dichloromethane (10.0 mL) was added tert-butyldimethylsilyl chloride (0.73 mL, 5.95 mmol, 1.20 equivalents) at 0°C. The reaction was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 50/1) to give tert-butyl((3-chloro-2-methyl-5-nitrobenzyl)oxy)dimethylsilane (1.20 g, 3.80 mmol, 76% yield) as a pale yellow oil.

Step 2: A mixture of tert-butyl((3-chloro-2-methyl-5-nitrobenzyl)oxy)dimethylsilane (1.50 g, 4.75 mmol, 1.00 equiv.), iron powder (795 mg, 14.2 mmol, 3.00 equiv.), and ammonium chloride (1.27 g, 23.7 mmol, 5.00 equiv.) in methanol (10.0 mL) and water (5.00 mL) was stirred at 80°C for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was added to water (100 mL) and stirred for 10 minutes. The mixture was extracted with ethyl acetate (3 x 60.0 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-4-methylaniline (900 mg, 3.15 mmol, 66% yield) as a yellow solid.

Step 3: To a solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-4-methylaniline (900 mg, 3.15 mmol, 1.00 equivalents) and pyridine (0.76 mL, 9.44 mmol, 3.00 equivalents) in acetonitrile (10.0 mL) was added phenyl chloroformate (0.43 mL, 3.46 mmol, 1.10 equivalents) at 0°C. The reaction was stirred at 25°C for 1 hour. The mixture was concentrated to give a residue. Water (100 mL) was added and the mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate (3 x 60.0 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 10/1) to obtain phenyl(3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-4-methylphenyl)carbamate (900 mg, 2.22 mmol, 70% yield) as a yellow solid.

Step 4: To a solution of 3-(6-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride VI (359 mg, 1.31 mmol, 1.00 equivalents, hydrochloride salt) and triethylamine (0.73 mL, 5.25 mmol, 4.00 equivalents) in dimethylformamide (5.00 mL) was added phenyl(3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-4-methylphenyl)carbamate (800 mg, 1.97 mmol, 1.50 equivalents). The reaction was stirred at 25°C for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase preparative HPLC to give 1-(3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)urea (350 mg, 598 μmol, 45% yield) as a white solid.

Step 5: To a solution of 1-(3-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)urea (350 mg, 598 μmol, 1.00 equiv.) in tetrahydrofuran (5.00 mL) was added tetrabutylammonium fluoride trihydrate (283 mg, 897 μmol, 1.50 equiv.). The reaction was stirred at 25°C for 2 hours. Saturated aqueous ammonium chloride (20.0 mL) was added to quench the reaction, and the mixture was poured into water (60.0 mL) and stirred for 10 minutes. The aqueous layer was extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC to give 1-(3-chloro-5-(hydroxymethyl)-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)urea (180 mg, 382 μmol, 64% yield) as a white solid.

Step 6: To a solution of 1-(3-chloro-5-(hydroxymethyl)-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)urea (150 mg, 318 μmol, 1.00 equivalents) in dichloromethane (1.00 mL) was added manganese dioxide (110 mg, 1.27 mmol, 4.00 equivalents). The reaction was stirred at 25°C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC to give compound 156 (37.38 mg, 72.6 μmol, 23% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 10.20 (s, 1H), 9.21 (s, 1H), 7.94 (d, J = 2.3 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.70 - 7.64 (m, 1H), 7.62 - 7.52 (m, 2H), 7.16 - 7.02 (m, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.52 - 4.36 (m, 3H), 4.36 (br s, 1H), 2.97 - 2.82 (m, 1H), 2.69 - 2.60 (m, 1H), 2.58 - 2.55 (m, 3H), 2.47 - 2.33 (m, 1H), 2.06 - 1.96 (m, 1H). MS (ESI) m/z 469.2 [M+H] ⁺

Compound 157: Prepared using General Procedure A with Variant iii) in 66% yield from Compound VI using phenyl (5-chloro-6-methylpyridin-3-yl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 9.83 (s, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.66 (s, 1H), 7.56 (s, 2H), 7.40 (br s, 1H), 5.16 - 5.06 (m, 1H), 4.41 - 4.27 (m, 4H), 2.96 - 2.84 (m, 1H), 2.59 (br d, J = 18.2 Hz, 1H), 2.54 (s, 3H), 2.43 - 2.33 (m, 1H), 2.04 - 1.94 (m, 1H). MS (ESI) m/z 442.2 [M+H] ⁺

Scheme for the preparation of phenyl(5-chloro-6-methylpyridin-3-yl)carbamate.

Step 1: A mixture of 3-chloro-2-methyl-5-nitropyridine (500 mg, 2.90 mmol, 1.00 equiv.), iron powder (1.13 g, 20.3 mmol, 7.00 equiv.), and ammonium chloride (1.08 g, 20.3 mmol, 7.00 equiv.) in methanol (5.00 mL) and water (5.00 mL) was stirred at 80°C for 2 hours. The mixture was filtered over Celite, and the filtrate was concentrated under reduced pressure to give 5-chloro-6-methylpyridin-3-amine (500 mg, crude) as a brown oil, which was used directly in the next step.

Step 2: To a solution of 5-chloro-6-methylpyridin-3-amine (200 mg, 1.40 mmol, 1.00 equiv.) and pyridine (0.34 mL, 4.21 mmol, 3.00 equiv.) in acetonitrile (2.00 mL) was added phenyl chloroformate (264 μL, 2.10 mmol, 1.50 equiv.). The reaction was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. Ethyl acetate (30.0 mL) and water (50.0 mL) were added, and the organic layer was separated. The aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain phenyl (5-chloro-6-methylpyridin-3-yl)carbamate (320 mg, 1.17 mmol, 83% yield) as a pale yellow solid.

Compound 158: Prepared using General Procedure A with Variant iii) in 57% yield from Compound VI using phenyl(2,6-dimethylpyridin-4-yl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 9.16 (br s, 1H), 8.19 (s, 1H), 7.66 (s, 1H), 7.57 (s, 2H), 7.16 (br t, J = 5.7 Hz, 1H), 7.11 (s, 2H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.45 - 4.31 (m, 4H), 2.98 - 2.85 (m, 1H), 2.64 - 2.56 (m, 1H), 2.46 - 2.37 (m, 1H), 2.32 (s, 6H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 422.1 [M+H] ⁺

Scheme for the preparation of phenyl(2,6-dimethylpyridin-4-yl)carbamate.

Step 1: To a solution of 2,6-dimethylpyridin-4-amine (1.00 g, 8.19 mmol, 1.00 equiv.) in acetonitrile (20.0 mL) at 0°C, pyridine (3.30 mL, 40.9 mmol, 5.00 equiv.) and phenyl chloroformate (1.54 mL, 12.2 mmol, 1.50 equiv.) were added. The reaction was stirred at 25°C for 0.5 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase HPLC to give phenyl (2,6-dimethylpyridin-4-yl)carbamate (600 mg, 2.48 mmol, 30% yield) as a yellow solid.

Compound 159: Prepared using General Procedure A with Variant iii) in 41% yield from Compound VI using phenyl(3-(difluoromethoxy)-4-methylphenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (br s, 1H), 8.82 (s, 1H), 7.66 (s, 1H), 7.57 (s, 2H), 7.43 (s, 1H), 7.09 (t, J =74.0 Hz, 1H), 7.14 - 7.07 (m, 2H), 6.83 (br t, J = 6.0 Hz, 1H), 5.12 (dd, J = 5.1, 13.2 Hz, 1H), 4.49 - 4.26 (m, 4H), 3.00 - 2.84 (m, 1H), 2.64 - 2.57 (m, 1H), 2.40 (dq, J = 4.6, 13.2 Hz, 1H), 2.14 (s, 3H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 473.1 [M+H] ⁺

Scheme for the preparation of phenyl(3-(difluoromethoxy)-4-methylphenyl)carbamate.

Step 1: To a solution of 2-methyl-5-nitrophenol (5.00 g, 32.7 mmol, 1.00 equiv.) and sodium 2-chloro-2,2-difluoroacetate (12.4 g, 81.6 mmol, 2.50 equiv.) in dimethylformamide (50.0 mL) was added cesium carbonate (21.3 g, 65.3 mmol, 2.00 equiv.) in small portions. The reaction was stirred at 100°C for 2 hours. The mixture was diluted with water (800 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (80.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 10/1) to obtain 2-(difluoromethoxy)-1-methyl-4-nitrobenzene (5.35 g, 26.3 mmol, 81% yield) as a clear oil.

Step 2: To a solution of 2-(difluoromethoxy)-1-methyl-4-nitrobenzene (4.85 g, 23.8 mmol, 1.00 equiv.) and ammonium chloride (6.39 g, 119 mmol, 5.00 equiv.) in methanol (40.0 mL) and water (40.0 mL), iron powder (4.00 g, 71.6 mmol, 3.00 equiv.) was added in small portions. The reaction was stirred at 80°C for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-(difluoromethoxy)-4-methylaniline (2.75 g, crude) as a brown oil, which was used directly in the next step.

Step 3: To a solution of 3-(difluoromethoxy)-4-methylaniline (1.00 g, 5.78 mmol, 1.00 equiv.) and pyridine (1.40 mL, 17.3 mmol, 3.00 equiv.) in acetonitrile (10.0 mL), phenyl chloroformate (1.09 mL, 8.66 mmol, 1.50 equiv.) was added dropwise. The reaction was stirred at 25°C for 12 hours. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 10/1) to obtain phenyl(3-(difluoromethoxy)-4-methylphenyl)carbamate (1.50 g, 5.11 mmol, 89% yield) as a yellow solid.

Compound 160: Prepared using General Procedure A with Variant iii) in 19% yield from Compound VI using phenyl (3-chloro-4-methyl-5-((4-methylmorpholin-3-yl)methyl)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (br s, 1H), 8.74 (s, 1H), 7.66 (s, 1H), 7.57 (s, 3H), 7.02 (d, J = 2.0 Hz, 1H), 6.82 (br t, J = 5.6 Hz, 1H), 5.12 (dd, J = 5.2, 13.2 Hz, 1H), 4.50 - 4.26 (m, 4H), 3.68 - 3.59 (m, 1H), 3.57 - 3.49 (m, 1H), 3.17 (dd, J = 7.8, 11.2 Hz, 1H), 3.07 (br dd, J = 3.4, 13.2 Hz, 1H), 2.98 - 2.84 (m, 1H), 2.72 - 2.57 (m, 3H), 2.43 - 2.37 (m, 2H), 2.34 (s, 3H), 2.29 - 2.17 (m, 5H), 2.01 (dt, J = 1.8, 6.2 Hz, 1H). MS (ESI) m/z 554.2 [M+H] ⁺

Scheme for the preparation of phenyl(3-chloro-4-methyl-5-((4-methylmorpholin-3-yl)methyl)phenyl)carbamate.

Step 1: A mixture of 2-methyl-5-nitrobenzoic acid (20.0 g, 110 mmol, 1.00 equiv.) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (21.8 g, 110 mmol, 1.00 equiv.) in sulfuric acid (20.0 mL) was stirred at 80°C for 10 hours. With stirring, the mixture was poured into ice water (approximately 300 mL). The resulting precipitate was collected by filtration and washed with water to give 3-chloro-2-methyl-5-nitrobenzoic acid (24.0 g, crude) as a white solid, which was used directly in the next step.

Step 2: To a solution of 3-chloro-2-methyl-5-nitrobenzoic acid (24.0 g, 111 mmol, 1.00 equiv.) in tetrahydrofuran (200 mL) was added borane dimethyl sulfide complex (10.0 M, 22.3 mL, 2.00 equiv.) at 0°C. The reaction was stirred at 25°C for 10 hours. Water (50.0 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (3-chloro-2-methyl-5-nitrophenyl)methanol (23.0 g, 111 mmol, crude) as a white solid, which was used directly in the next step.

Step 3: To a solution of (3-chloro-2-methyl-5-nitrophenyl)methanol (23.0 g, 114 mmol, 1.00 equiv.) in dichloromethane (200 mL) was added thionyl chloride (41.4 mL, 570 mmol, 5.00 equiv.). The reaction was stirred at 25°C for 10 hours. The mixture was poured into ice water (50.0 mL) and extracted with dichloromethane (3 x 150 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2 x 50.0 mL) and brine (50.0 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene (26.0 g, 114 mmol, crude) as a yellow oil.

Step 4: To a solution of 60% pure sodium hydride (1.00 g, 25.0 mmol, 1.10 equiv.) in dimethylformamide (50.0 mL) was added diethyl 2-acetamidomalonate (5.92 g, 27.3 mmol, 1.20 equiv.) at 0°C. After 5 minutes, 1-chloro-3-(chloromethyl)-2-methyl-5-nitrobenzene (5.00 g, 22.7 mmol, 1.00 equiv.) was added. The reaction was stirred at 25°C for 10 hours. Water (50.0 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3 x 50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give diethyl 2-acetamido-2-(3-chloro-2-methyl-5-nitrobenzyl)malonate (9.20 g, 27.3 mmol, crude) as a yellow solid.

Step 5: To a solution of 2-amino-3-(3-chloro-2-methyl-5-nitrophenyl)propanoic acid (3.00 g, 11.6 mmol, 1.00 equiv.) in tetrahydrofuran (30.0 mL), borane dimethyl sulfide complex (10.0 M, 3.48 mL, 3.00 equiv.) was added. The reaction was stirred at 70°C for 10 hours. Methanol (20.0 mL) was added at 0°C to quench the reaction, and the mixture was concentrated under reduced pressure to give 2-amino-3-(3-chloro-2-methyl-5-nitrophenyl)propan-1-ol (3.00 g, 11.6 mmol, crude) as a yellow oil.

Step 6: To a solution of 2-amino-3-(3-chloro-2-methyl-5-nitrophenyl)propan-1-ol (3.00 g, 12.3 mmol, 1.00 equiv.) and triethylamine (2.05 mL, 14.7 mmol, 1.20 equiv.) in tetrahydrofuran (30.0 mL) at 0°C, 2-chloroacetyl chloride (1.17 mL, 14.7 mmol, 1.20 equiv.) was added. The reaction was stirred at 25°C for 1 hour. Water (10.0 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain 2-chloro-N-(1-(3-chloro-2-methyl-5-nitrophenyl)-3-hydroxypropan-2-yl)acetamide (1.30 g, 4.05 mmol, 33% yield) as a yellow solid.

Step 7: To a solution of 2-chloro-N-(1-(3-chloro-2-methyl-5-nitrophenyl)-3-hydroxypropan-2-yl)acetamide (1.20 g, 3.74 mmol, 1.00 equivalents) in tert-butyl alcohol (3.00 mL) was added potassium tert-butoxide (839 mg, 7.47 mmol, 2.00 equivalents). The reaction was stirred at 100°C for 0.5 hours. The mixture was concentrated under reduced pressure to provide a residue. The residue was diluted with water (10.0 mL) and extracted with ethyl acetate (3 x 30.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 5/1) to obtain 5-(3-chloro-2-methyl-5-nitrobenzyl)morpholin-3-one (0.250 g, 878 μmol, crude) as a yellow solid.

Step 8: To a solution of 5-(3-chloro-2-methyl-5-nitrobenzyl)morpholin-3-one (240 mg, 843 μmol, 1.00 equiv.) in tetrahydrofuran (3.00 mL) was added borane dimethyl sulfide complex (10.0 M, 253 μL, 3.00 equiv.). The reaction was stirred at 70°C for 10 hours. Methanol (10.0 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure to give 3-(3-chloro-2-methyl-5-nitrobenzyl)morpholine (0.200 g, 843 μmol, crude) as a yellow solid.

Step 9: To a solution of 3-(3-chloro-2-methyl-5-nitrobenzyl)morpholine (0.150 g, 554 μmol, 1.00 equiv.) and 37% pure formaldehyde (0.90 mL, 12.1 mmol, 21.8 equiv.) in methanol (2.00 mL) was added acetic acid (63.4 μL, 1.11 mmol, 2.00 equiv.). After 0.5 h, sodium cyanoborohydride (174 mg, 2.77 mmol, 5.00 equiv.) was added, and the reaction was stirred at 25°C for 10 h. Water (15.0 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (3 x 30.0 mL). The combined organic layers were washed with brine (15.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC to yield 3-(3-chloro-2-methyl-5-nitrobenzyl)-4-methylmorpholine (0.140 g, 492 μmol, 89% yield) as a yellow oil.

Step 10: A mixture of 3-(3-chloro-2-methyl-5-nitrobenzyl)-4-methylmorpholine (0.140 g, 492 μmol, 1.00 equiv.), iron powder (137 mg, 2.46 mmol, 5.00 equiv.), and ammonium chloride (26.3 mg, 492 μmol, 1.00 equiv.) in ethanol (2.00 mL) and water (1.00 mL) was stirred at 60°C for 10 hours. The mixture was concentrated under reduced pressure to give a residue. Water (15.0 mL) was added, and the mixture was extracted with ethyl acetate (3 x 25.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3-chloro-4-methyl-5-((4-methylmorpholin-3-yl)methyl)aniline (0.100 g, 393 μmol, 80% yield) as a yellow oil.

Step 11: To a solution of 3-chloro-4-methyl-5-((4-methylmorpholin-3-yl)methyl)aniline (0.100 g, 393 μmol, 1.00 equiv.) and potassium carbonate (109 mg, 785 μmol, 2.00 equiv.) in acetone (2.00 mL) was added phenyl chloroformate (59.0 μL, 471 μmol, 1.20 equiv.) at 0°C. The reaction was stirred at 25°C for 10 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (3 x 25.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give phenyl (3-chloro-4-methyl-5-((4-methylmorpholin-3-yl)methyl)phenyl)carbamate (0.140 g, 373 μmol, crude) as a yellow oil.

Compound 161: Prepared using General Procedure A with Variant iii) in 27% yield from Compound VI using phenyl (3-chloro-5-((1-methylpyrrolidin-3-yl)methoxy)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.11 - 10.85 (m, 1H), 10.67 (br s, 1H), 9.15 (br s, 1H), 7.67 (s, 1H), 7.60 - 7.50 (m, 2H), 7.13 (br s, 1H), 7.09 (br d, J = 8.1 Hz, 1H), 6.57 (t, J = 2.1 Hz, 1H), 5.10 - 5.01 (m, 1H), 5.12 - 4.98 (m, 1H), 4.48 - 4.32 (m, 4H), 4.09 - 3.97 (m, 2H), 3.52 - 3.40 (m, 1H), 3.27 - 2.98 (m, 2H), 2.96 - 2.84 (m, 2H), 2.81 (br s, 3H), 2.68 - 2.59 (m, 1H), 2.49 - 2.34 (m, 2H), 2.31 - 2.11 (m, 1H), 2.09 - 2.00 (m, 1H), 1.99 - 1.72 (m, 1H). MS (ESI) m/z 540.3 [M+H] ⁺

Scheme for the preparation of phenyl(3-chloro-5-((1-methylpyrrolidin-3-yl)methoxy)phenyl)carbamate.

Step 1: Under a nitrogen atmosphere, methylsulfamoyl chloride (1.50 mL, 19.4 mmol, 1.30 equiv.) was added dropwise to a solution of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (3.00 g, 14.9 mmol, 1.00 equiv.) and triethylamine (3.77 g, 37.3 mmol, 5.19 mL, 2.50 equiv.) in dichloromethane (30.0 mL) at 0°C. The reaction was stirred at 25°C for 2 hours. The mixture was diluted with ethyl acetate (100 mL) and water (150 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The organic layer was collected, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (4.00 g, crude) as a pale yellow oil.

Step 2: To a solution of tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (3.00 g, 10.8 mmol, 1.00 equiv.) in dimethylformamide (30.0 mL) was added 3-chloro-5-nitrophenol (2.05 g, 11.8 mmol, 1.10 equiv.) and cesium carbonate (10.5 g, 32.2 mmol, 3.00 equiv.). The reaction was stirred at 80°C for 12 hours. The mixture was diluted with ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 80.0 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain tert-butyl 3-((3-chloro-5-nitrophenoxy)methyl)pyrrolidine-1-carboxylate (3.80 g, 10.7 mmol, 99% yield) as a yellow oil.

Step 3: To a solution of tert-butyl 3-((3-chloro-5-nitrophenoxy)methyl)pyrrolidine-1-carboxylate (1.10 g, 3.08 mmol, 1.00 equivalents) in ethyl acetate (5.00 mL) was added hydrochloric acid in ethyl acetate (4 M, 10 mL). The reaction was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to provide 3-((3-chloro-5-nitrophenoxy)methyl)pyrrolidine (1.00 g, crude) as a yellow solid.

Step 4: To a solution of 3-((3-chloro-5-nitrophenoxy)methyl)pyrrolidine (1.50 g, 5.84 mmol, 1.00 equiv.) in 2,2,2-trifluoroethanol (10.0 mL) was added paraformaldehyde (0.80 mL, 29.2 mmol, 5.00 equiv.). The reaction was stirred at 60°C for 0.5 h. Sodium borohydride (442 mg, 11.7 mmol, 2.00 equiv.) was added in small portions and the reaction was stirred at 60°C for 1 h. The reaction was quenched with saturated ammonium chloride solution (10.0 mL) and concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase preparative HPLC to yield 3-((3-chloro-5-nitrophenoxy)methyl)-1-methylpyrrolidine (1.50 g, 4.99 mmol, 86% yield) as a yellow oil.

Step 5: To a solution of 3-((3-chloro-5-nitrophenoxy)methyl)-1-methylpyrrolidine (1.20 g, 4.43 mmol, 1.00 equiv.) in methanol (6.00 mL) and water (6.00 mL), ammonium chloride (1.66 g, 31.0 mmol, 7.00 equiv.) and iron powder (1.73 g, 31.0 mmol, 7.00 equiv.) were added. The reaction was stirred at 80°C for 2 hours. The mixture was filtered over Celite, and the filtrate was concentrated under reduced pressure to provide 3-chloro-5-((1-methylpyrrolidin-3-yl)methoxy)aniline (1.00 g, crude) as a brown oil.

Step 6: To a solution of phenyl chloroformate (0.28 mL, 2.24 mmol, 1.20 equiv.) in acetonitrile (5.00 mL), pyridine (0.45 mL, 5.61 mmol, 3.00 equiv.) and 3-chloro-5-((1-methylpyrrolidin-3-yl)methoxy)aniline (450 mg, 1.87 mmol, 1.00 equiv.) were added. The reaction was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by reverse-phase preparative HPLC to provide phenyl (3-chloro-5-((1-methylpyrrolidin-3-yl)methoxy)phenyl)carbamate (630 mg, 1.64 mmol, 88% yield) as a pale yellow solid.

Compound 162: Prepared using General Procedure A with Variant iii) in 33% yield from Compound VI using phenyl (3-chloro-5-((1-methylpyrrolidin-3-yl)oxy)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.15 (br d, J = 4.3 Hz, 1H), 10.98 (s, 1H), 10.63 (br s, 1H), 9.58 - 9.41 (m, 1H), 7.64 (s, 1H), 7.55 (d, J = 0.8 Hz, 2H), 7.25 - 7.17 (m, 1H), 7.28 - 7.13 (m, 1H), 7.12 - 7.04 (m, 1H), 6.60 (d, J = 1.9 Hz, 1H), 5.19 - 5.02 (m, 2H), 4.47 - 4.26 (m, 4H), 3.97 - 3.69 (m, 1H), 3.40 - 3.20 (m, 1H), 3.18 - 3.05 (m, 1H), 2.97 - 2.88 (m, 1H), 2.87 - 2.80 (m, 3H), 2.63 - 2.56 (m, 1H), 2.46 - 2.33 (m, 1H), 2.31 - 2.14 (m, 1H), 2.09 - 1.96 (m, 2H). MS (ESI) m/z 526.2 [M+H] ⁺

Scheme for the preparation of phenyl(3-chloro-5-((1-methylpyrrolidin-3-yl)oxy)phenyl)carbamate.

Step 1: To a solution of tert-butyl 3-(3-chloro-5-nitro-phenoxy)pyrrolidine-1-carboxylate (2.00 g, 5.83 mmol, 1.00 equiv.) in ethyl acetate (10.0 mL) was added hydrochloric acid in ethyl acetate (4 M, 20.0 mL, 13.7 equiv.). The reaction was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to provide 3-(3-chloro-5-nitrophenoxy)pyrrolidine (1.40 g, 5.77 mmol, 98% yield) as a yellow oil.

Step 2: To a solution of 3-(3-chloro-5-nitrophenoxy)pyrrolidine (1.00 g, 4.12 mmol, 1.00 equiv.) in methanol (6.00 mL) was added 37% pure paraformaldehyde (6.00 mL, 80.6 mmol, 19.60 equiv.), acetic acid (0.23 mL, 4.11 mmol, 1.00 equiv.), and sodium cyanoborohydride (1.29 g, 20.6 mmol, 5.00 equiv.) in small portions. The reaction was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to provide a residue. The residue was first purified by silica gel column chromatography (petroleum ether/ethyl acetate to ethyl acetate/methanol = 3/1 to 0/1) and then by reverse-phase preparative HPLC to give 3-(3-chloro-5-nitrophenoxy)-1-methylpyrrolidine (470 mg, 1.83 mmol, 44% yield) as a yellow oil.

Step 3: To a solution of 3-(3-chloro-5-nitrophenoxy)-1-methylpyrrolidine (460 mg, 1.79 mmol, 1.00 equiv.) in methanol (15.0 mL) and water (8.00 mL), iron powder (300 mg, 5.37 mmol, 3.00 equiv.) and ammonium chloride (479 mg, 8.95 mmol, 5.00 equiv.) were added in small portions. The reaction was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure to give a residue, which was diluted with water (50.0 mL) and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-chloro-5-((1-methylpyrrolidin-3-yl)oxy)aniline (300 mg, crude) as a yellow oil, which was used directly in the next step.

Step 4: To a solution of 3-chloro-5-((1-methylpyrrolidin-3-yl)oxy)aniline (290 mg, 1.28 mmol, 1.00 equiv.) in acetonitrile (5.00 mL), pyridine (0.52 mL, 6.39 mmol, 5.00 equiv.) and phenyl chloroformate (0.19 mL, 1.54 mmol, 1.20 equiv.) were added in small portions. The reaction was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to give a residue that was purified by reverse-phase preparative HPLC to give phenyl (3-chloro-5-((1-methylpyrrolidin-3-yl)oxy)phenyl)carbamate (370 mg, 1.07 mmol, 83% yield) as a white solid.

Compound 163: Prepared using General Procedure A with Variant iii) in 59% yield from Compound VI using phenyl N-(6-tert-butyl-3-pyridyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (s, 1H), 8.79 (s, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.23 (s, 1H), 7.86 - 7.81 (m, 1H), 7.67 (s, 1H), 7.57 (d, J = 1.0 Hz, 2H), 7.29 (d, J = 8.6 Hz, 1H), 6.91 (t, J = 6.0 Hz, 1H), 5.16 - 5.09 (m, 1H), 4.49 - 4.27 (m, 4H), 2.98 - 2.85 (m, 1H), 2.66 - 2.56 (m, 1H), 2.47 - 2.36 (m, 1H), 2.05 - 1.94 (m, 1H), 1.27 (s, 9H). MS (ESI) m/z 450.2 [M+H] ⁺

Scheme for the synthesis of phenyl N-(6-tert-butyl-3-pyridyl)carbamate.

Step 1: To a solution of 6-(tert-butyl)pyridin-3-amine (150 mg, 998 μmol, 1.00 equiv.) in acetonitrile (5.00 mL), pyridine (0.40 mL, 4.99 mmol, 5.00 equiv.) and phenyl chloroformate (0.15 mL, 1.20 mmol, 1.20 equiv.) were added. The reaction was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC to give phenyl (6-(tert-butyl)pyridin-3-yl)carbamate (230 mg, 850 μmol, 85% yield) as a yellow solid.

Compound 164: Prepared using General Procedure A with Variant iii) in 52% yield from Compound VI using phenyl(4-(trifluoromethoxy)pyridin-2-yl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97 (br s, 1H), 9.60 (s, 1H), 8.29 (d, J = 5.7 Hz, 1H), 8.15 - 8.03 (m, 1H), 7.66 (s, 1H), 7.62 - 7.54 (m, 3H), 6.98 - 6.90 (m, 1H), 5.11 (dd, J = 5.0, 13.3 Hz, 1H), 4.51 - 4.41 (m, 3H), 4.34 - 4.27 (m, 1H), 2.95 - 2.87 (m, 1H), 2.61 (br d, J = 2.3 Hz, 1H), 2.45 - 2.36 (m, 1H), 2.05 - 1.95 (m, 1H). MS (ESI) m/z 478.1 [M+H] ⁺

Scheme for the preparation of phenyl(4-(trifluoromethoxy)pyridin-2-yl)carbamate.

Step 1: To a solution of 4-(trifluoromethoxy)pyridin-2-amine (300 mg, 1.68 mmol, 1.00 equiv.) and pyridine (0.68 mL, 8.42 mmol, 5.00 equiv.) in acetonitrile (3.00 mL) was added phenyl chloroformate (0.25 mL, 2.02 mmol, 1.20 equiv.) dropwise at 0°C. The reaction was stirred at 25°C for 3 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC to give phenyl (4-(trifluoromethoxy)pyridin-2-yl)carbamate (350 mg, 1.17 mmol, 69% yield) as a white solid.

Compound 165: Prepared using General Procedure A with Variant iii) in 53% yield from Compound VI using phenyl (3-fluoro-5-(trifluoromethoxy)phenyl)carbamate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 9.25 (s, 1H), 7.66 (s, 1H), 7.56 (d, J = 0.9 Hz, 2H), 7.36 - 7.30 (m, 2H), 7.06 (t, J = 6.0 Hz, 1H), 6.83 (br d, J = 9.0 Hz, 1H), 5.11 (dd, J = 5.0, 13.3 Hz, 1H), 4.47 - 4.38 (m, 3H), 4.34 - 4.26 (m, 1H), 2.97 - 2.85 (m, 1H), 2.60 (td, J = 2.0, 15.3 Hz, 1H), 2.45 - 2.35 (m, 1H), 2.04 - 1.95 (m, 1H). MS (ESI) m/z 495.2 [M+H] ⁺

Scheme for the preparation of phenyl(3-fluoro-5-(trifluoromethoxy)phenyl)carbamate.

Step 1: To a solution of 3-fluoro-5-(trifluoromethoxy)aniline (200 mg, 1.03 mmol, 1.00 equiv) in acetonitrile (10.0 mL) at 0° C. were added pyridine (0.25 mL, 3.10 mmol, 3.02 equiv) and phenyl chloroformate (0.15 mL, 1.23 mmol, 1.20 equiv) in small portions. The reaction was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure to give a residue which was purified by reverse-phase HPLC to give phenyl (3-fluoro-5-(trifluoromethoxy)phenyl)carbamate (320 mg, 1.02 mmol, 99% yield) as a white solid.
Fluorescence polarization assay protocol

Compound activity was monitored in a fluorescence polarization (FP) homogeneous assay using 1-[5-({2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamido)ethoxy]ethyl}carbamoyl)pentyl]-3,3-dimethyl-2-[(1E,3E)-5-[(2E)-1,3,3-trimethyl-5-sulfo-2,3-dihydro-1H-indol-2-ylidene]penta-1,3-dien-1-yl]-3H-indol-1-ium-5-sulfonate as the fluorescent probe. Unless otherwise stated, all reagents were purchased from Sigma-Aldrich. Enzyme reactions were performed in a Perkin-Elmer Black 384-well ProxiPlate Plus (Cat. No. 6008269) in a total volume of 10 μL. Full-length wild-type cereblon CRBN (80.0 nM, 10 μL) was incubated in the presence (300 nL) or absence of compound in assay buffer containing 20 mM HEPES (pH 8.0), 150 NaCl, 0.5 mM TCEP, and 0.05% Tween® 20. Inhibitors were stored as 10 mM DMSO stock solutions in an inert environment (low humidity, protected from light, low oxygen, room temperature) using a storage pod system. Compounds and DMSO were dispensed using an Echo E5XX (Labcyte Inc., USA) to yield concentrations ranging from 300 to 0.937 or 3000 to 9.3 nM for 12 data point curves. Mutant YWAA CRBN (80.0 nM, 10 μL), which does not interact with the fluorescent probe, was used as a negative control for the assay. After a 30-minute incubation at room temperature, the assay was initiated by dispensing the probe to a final concentration of 5 nM (2.5 nL of a 20 μM stock solution) using an Echo E5XX. FP was measured after 12 hours using a Pherastar plate reader (BMG Labtech, Germany) with excitation at 590 nm and parallel and perpendicular light at 675 nm. FP signals were then normalized to the no-compound control (i.e., DMSO). Analysis and IC50 values were derived using Dotmatics (Dotmatics UK) software.
Table 2: IC50 values determined in a fluorescence polarization assay demonstrating cereblon binding

In some embodiments, the present disclosure is directed to compounds having an IC value of less than 1100 nM, i.e., compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 26, 26, 27, 28, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 82, 83, 84, 85, 86, 87 , 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 1 25, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 142, 144, 145, 146, 147, 148, 150, 151, 152, 154, 155, 156, 158, 159, 160, 161 and 162.
Immunofluorescence assay protocol

GSPT1 was selected and tested in an immunofluorescence assay to demonstrate its ability to bind and degrade specific proteins of interest.

CAL-51 cells were purchased from DSMZ (catalog no. ACC302), subcultured in 90% Dulbecco's MEM (4.5 g/L glucose, Gibco 11965) and 10% heat-inactivated FBS (BioConcept, 2-01F136I), and incubated at ₃₇ °C and 5% CO . For the assay, imaging microtiter plates, Cell Carrier 96 Ultra (Perkin Elmer 6055302), were pre-coated with fibronectin (Sigma F085, 30 μl at 0.2 μg/ml) in PBS (100 μl, Gibco 14190) for 45 minutes at room temperature, rinsed with PBS, and CAL-51 cells (30K cells/well) were plated and allowed to adhere overnight. Cells were treated with compounds for 6 hours, typically using serial dilutions ranging from 30 μM to 0.1 nM. Compounds were stored in a 10 mM DMSO stock solution. Vehicle (DMSO), positive (CC-885, 10 μM), and rescue controls (positive control and 0.2 μM bortezomib) were also included at this stage. Cells were then rinsed with PBS and fixed in 10% formalin solution (50 μl, Sigma HT5011) for 20 minutes at room temperature. After three consecutive PBS washes (100 μl), cells were permeabilized in 0.1% Triton® X-100 in PBS (Sigma 93443, 50 μl) for 15 minutes at room temperature. After three more PBS washes, 50 μl of blocking buffer (1% BSA, Sigma A4503 in PBS) was added for 45 minutes to reduce signal-to-noise.

The primary antibody (human GSPT1, Sigma HPA052488) was diluted in blocking buffer (1/300 dilution, 35 μL/well) and incubated with the cells overnight at 4°C. After three PBS washes, Alexa-fluor 488-conjugated secondary antibody (Invitrogen, A32731, 1/1000 dilution), Alexa-fluor 647-Phalloidin (Invitrogen, A22287, 1/200 dilution), and DAPI (Thermo, #62248, 1/1000 dilution) were diluted in blocking buffer and incubated with the samples for 2 hours at room temperature. After the final three PBS washes, the samples were stored in 100 μl of PBS in the dark until assayed. Image acquisition was performed with an Operetta High-Content Imager (Perkin-Elmer). Fluorescence intensities of Alexa-Fluor 488 (GSPT1), Alexa-Fluor 647 (actin), and DAPI (nuclei) were measured. A custom algorithm was developed for determining the _DC50 value of GSPT1, implemented in the PerkinElmer imaging software Harmony-Acapella®. After user-defined settings of adjustment parameters, analysis was performed identically for all image fields without human intervention. Nuclear DAPI staining was used to determine cell location using a standard nuclei detection module. Segmentation artifacts were removed by threshold-based filters for area, circularity, and intensity. Cell outlines were similarly determined from the sum of the normalized, smoothed DAPI and actin channels starting from each nucleus. The Alexa-Fluor 488 (GSPT1) signal intensity in each cell was finally measured to obtain the average intensity per cell. GSPT1 degradation (DC ₅₀ ) was calculated after normalization to the control, and data were imported into the CDD vault database using nonlinear regression.
Table 3: Activity against GSPT1 degradation

Table 3 assigns each compound a code indicating its ability to degrade GSPT1: A, B, or C. According to the code, A represents a DC50 value of ≦100 nM, B represents a DC50 value of >100 nM and ≦300 nM, and C represents a DC50 value of >300 nM.

In some embodiments, a compound of any of Formulas I-IV exhibits a DC50 value of 300 nM or less, i.e., the compound has the code A and B. In some embodiments, the compound is selected from the group consisting of 8, 20, 30, 31, 33, 38, 41, 42, 46, 47, 56, 59, 61, 68, 71, 75, 76, 77, 78, 82, 85, 89, 90, 101, 106, 109, 115, 118, 119, 121, 122, 125, 127, 129, 132, 138, 139, 140, 141, 142, 143, 144, 145, 151, 155, 160, and 163.

In some embodiments, a compound of any of Formulas I-IV exhibits a DC50 value of 100 nM or less, i.e., the compound has the code A. In some embodiments, the compound is selected from the group consisting of 8, 20, 30, 33, 46, 47, 56, 61, 71, 76, 77, 78, 82, 90, 118, 119, 122, 125, 127, 129, 132, 138, 139, 140, 141, 142, 144, 145, 151, 160, and 163.

3D spheroid experiments - HMEC

Human mammary epithelial cells (HMECs) were engineered to express either EGFP-tagged c-myc or EGFP alone (non-myc) (distinct from but similar to Kessler JD et al, Science. 2012 Jan 20; 335(6066):348-53. doi: 10.1126/science.1212728; Hsu TY et al, Nature. 2015 Sep 17; 525(7569):384-8. doi: 10.1038/nature14985). Engineered cells were seeded at 1000 (myc) or 4000 (non-myc) cells/well in 384 ultra-low attachment plates in a total volume of 40 μL of HMEC cell culture medium (DMEM/F12 + 10% HI-FBS + 15 mM HEPES + 0.5 μg/ml hydrocortisone + 10 μg/ml insulin + 20 ng/ml EGF). Plates were spun at 1200 rpm for 5 minutes at room temperature to ensure cells were centered in the well and incubated at 37°C for 48 hours before compound stimulation. On day 2 (48 hours after seeding), cells were imaged (bright field and EGFP fluorescence) using a Celigo imaging cytometer before compound stimulation. For primary screening, compounds were added at three concentrations (1.25, 10, and 30 μM) in 120 nL using an ECHO acoustic dispenser and incubated at 37° C. for 5 days after rotation at 2000 rpm for 2 minutes at room temperature. For counterscreening and IC50 concentration establishment, 12 doses were prepared starting at 30 μM in 3-fold dilutions and added to the cells in 120 nL using an ECHO acoustic dispenser. The plates were rotated at 2000 rpm for 2 minutes at room temperature before incubation at 37° C. for 5 days. On day 7, cells were imaged (bright field and EGFP fluorescence) on a Celigo imaging cytometer before measuring cell viability using CellTiterGlo3D. CellTiterGlo3D reagent was added at 30 μL/well and incubated at room temperature for 30 minutes. After 30 minutes of incubation, luminescence readings were recorded using a Perkin Elmer EnVision reader.
Table 4: 3D spheroid assay

Table 4 assigns each compound a code indicating its EC50 value in the myc-HMEC and non-myc-HMEC assays: D, E, F, or G. According to the code, D represents an EC50 value of ≦400 nM in the myc-HMEC assay, E represents an EC50 value of >400 nM and ≦2000 nM in the myc-HMEC assay, F represents an EC50 value of >2000 nM in the myc-HMEC assay, and G represents an EC50 value of >10,000 nM in the non-myc-HMEC assay.

In some embodiments, any of the compounds of Formulas I-IV exhibits an EC50 value of 2000 nM or less, i.e., the compounds have codes D and E. In some embodiments, the compounds are selected from the group consisting of 8, 20, 30, 31, 33, 38, 41, 42, 46, 47, 56, 59, 61, 68, and 71.

In some embodiments, any of the compounds of Formulas I-IV exhibits an EC50 value of 400 nM or less, i.e., the compounds have the code D. In some embodiments, the compounds are selected from the group consisting of 8, 30, 33, 38, 56, 61, and 71.

In vivo efficacy study - tumor growth inhibition (Figure 1)

CAL51 cells (DSMZ-ACC-302) were maintained in vitro in DMEM medium supplemented with 20% heat-inactivated FBS at 37°C in an atmosphere of 5% _CO2 in air. Cells (5 million) resuspended in 0.2 mL of PBS (50:50) containing Matrigel were inoculated into female SCID beige mice and allowed to grow to a size of 150 ^mm3 . Mice were administered daily i.p. with vehicle or Compound 8 (3, 10, and 30 mg per kilogram). Compound formulations were prepared fresh daily in 0.5% MC4000 and 0.2% Tween® 80. Mice were dosed for 24 days, and tumor volumes were measured every 3 days.
In vivo efficacy study - tumor growth inhibition in the MDA-MB-213 model (Figure 2)

MDA-MB-231 cells were maintained in vitro in DMEM medium supplemented with 20% heat-inactivated FBS at 37°C in an atmosphere of 5% _CO2 in air. Cells (10 million) resuspended in 0.2 mL of PBS (50:50) containing Matrigel were inoculated into female BALB/c nude mice and allowed to grow to a size of 150 ^mm3 . Mice received vehicle or Compound 82 i.p. daily (10 mg and 37 mg per kilogram i.p. or 37 mg per kilogram subcutaneously). Compound formulations were prepared fresh daily in 0.5% MC4000 and 0.2% Tween® 80 for i.p. administration and 5% DMSO/75% (40% HP-β-CD in 0.1 M HCl)/20% purified water for subcutaneous administration. Mice were dosed for 24 days and tumor volumes were measured every 3 days.
Determination of CK1alpha/Ikaros/Alolos/ZFP91 selectivity by Western blot assay

MM1S cells were purchased from ATCC (catalog number CRL-2974) and subcultured in 90% RPMI 1640 medium containing 10% FBS supplemented with 1x P/S and incubated at 37°C and 5% CO2. Compounds were stored as 10 mM DMSO stock solutions. For the assay, MM1S cells (3 million cells/well) were plated in 6-well plates and incubated overnight. Cells were treated for 6 hours with individual compounds using serial dilutions: 0.3 μM, 3 μM, and 30 μM, as well as a vehicle-only (DMSO) control. Subsequently, the medium containing the suspended cells was transferred to a 15 mL conical tube, and the wells were thoroughly rinsed twice with ice-cold PBS and combined with the cell suspension in each 15 mL conical tube. The cells were spun down, the supernatant was aspirated, and the pellet was resuspended in ice-cold PBS and transferred to a microfuge tube. The cells were spun down, the supernatant aspirated, and the pellet resuspended in 120 μL of RIPA lysis buffer supplemented with protease and phosphatase inhibitors. The cell lysate was incubated on ice for 20 minutes and then centrifuged at >20,000 x g for 5 minutes. The supernatant was transferred to a new microtube and stored at -80°C. Total protein concentration was determined using a BCA assay with a BSA standard curve, and all sample concentrations were adjusted to 1 mg/mL. 25 μL of 4x LDS sample buffer supplemented with 100 mM DTT was added to 75 μL of sample. The sample was centrifuged (8,000 x g, 1 minute) and incubated at 95°C for 5 minutes, followed by another centrifugation step (8,000 x g, 1 minute). 20 μL of each sample was loaded onto a 4-12% gel along with protein molecular weight markers. The gel was run in the presence of MOPS buffer for 30 minutes at 80 volts, then for 1.5 hours at 120 volts, followed by transfer of proteins onto the surface of a nitrocellulose membrane at 20 volts for 7 minutes using an iBlot2 Gel Transfer Device. The membrane was then cut horizontally into two pieces ranging from 80 to 50 kDa and 50 to 25 kDa. Blocking of the membrane was performed by gentle shaking in 5% (w/v) nonfat dry milk in TSB-T for 1 hour at room temperature. All primary antibodies were used at 1/1000 in 5% (w/v) BSA in TBST and incubated with the membrane overnight at 4°C. After three 5-minute washes with 1x TBST, HRP-conjugated secondary antibodies diluted in 5% (w/v) BSA/TBST (goat anti-Rb IgG, 1/10,000 dilution; goat anti-mouse IgG, 1/5,000 dilution) were added for 1 hour at room temperature. After three 5-minute washes with 1x TBST, the membrane was incubated with ECL reagents for 1 minute at room temperature. The chemiluminescent signal was then detected using the LAS-4000 system with default settings, and the signal was quantified using Image Studio Lite software (version 5.2). A portion of the membrane previously incubated with an antibody against CK1 alpha was incubated with stripping buffer for 30 min, then washed three times with TBST (5 min each), blocked with 5% (w/v) nonfat dry milk for 1 h, and stripped of the antibody by incubation with a primary antibody against GAPDH overnight at 4° C. Subsequent washes, incubation with secondary antibody, and signal acquisition were performed as described above.
Table 5: Selectivity for related zinc finger proteins:

Table 5 assigns each compound a code indicating its ability to degrade IKZF1, IKZF3, CK1alpha, and ZFP91: A, B, C, D, E, or F. According to the code, A indicates no degradation observed at 30 μM, B indicates slight degradation (less than 20%) at 30 μM, C indicates weak degradation (less than 50%) at 30 μM, D indicates degradation (>90%) at 30 μM, E indicates degradation at 3 μM (>90%), and F indicates degradation at 0.3 μM (>90%).

Claims (14)

A compound of formula IV, V, VI or VII , or a pharmaceutically acceptable salt or stereoisomer thereof

wherein
W, ^W1 , ^W2 , ^W3 are


are independently selected from
A compound, or a pharmaceutically acceptable salt or stereoisomer thereof. W is,


2. The compound of claim 1 , wherein: 10. A composition comprising a compound according to claim 1 or 2 , or a pharmaceutically acceptable salt or stereoisomer thereof. The composition of claim 3 further comprising a pharmaceutically acceptable carrier. 5. The composition of claim 3 or 4 , further comprising a second therapeutically active agent. A composition comprising a compound according to claim 1 or 2 or a composition according to any one of claims 3 to 5 for use in therapy. A composition comprising a compound according to claim 1 or 2 or a composition according to any one of claims 3 to 5 for use in treating a disease associated with GSPT1. A composition comprising a compound according to claim 1 or 2 or a composition according to any one of claims 3 to 5 for use in the treatment of cancer. The composition of claim 8 , wherein the cancer is breast cancer. A composition comprising a compound according to claim 1 or 2 or a composition according to any one of claims 3 to 5 for binding to cereblon . The composition of claim 10 for treating cancer . The composition of claim 11 , wherein the cancer is breast cancer. A composition comprising a compound according to claim 1 or 2 or a composition according to any one of claims 3 to 5 for treating cancer in a subject. 14. The composition of claim 13 , wherein the compound of claim 1 or 2 , or a pharmaceutically acceptable salt or stereoisomer thereof, binds to the cereblon.